Managing the immune microenvironment of osteosarcoma: the outlook for osteosarcoma treatment

Liu, W. et al. TRIM22 inhibits osteosarcoma progression through destabilizing NRF2 and thus activation of ROS/AMPK/mTOR/autophagy signaling. Redox Biol. 53, 102344 (2022).

Li, H. B. et al. METTL14-mediated epitranscriptome modification of MN1 mRNA promote tumorigenicity and all-trans-retinoic acid resistance in osteosarcoma. EBioMedicine 82, 104142 (2022).

Huang, X., Wang, L., Guo, H., Zhang, W. & Shao, Z. Single-cell transcriptomics reveals the regulative roles of cancer associated fibroblasts in tumor immune microenvironment of recurrent osteosarcoma. Theranostics 12, 5877–5887 (2022).

Yu, L. et al. Circular RNA circFIRRE drives osteosarcoma progression and metastasis through tumorigenic-angiogenic coupling. Mol. Cancer 21, 167 (2022).

Tsukamoto, S. et al. Effect of adjuvant chemotherapy on periosteal osteosarcoma: a systematic review. Jpn. J. Clin. Oncol. 52, 888–896 (2022).

Horkoff, M. J. et al. A population-based analysis of the presentation and outcomes of pediatric patients with osteosarcoma in Canada: a report from CYP-C. Can. J. Surg. 65, E527–e533 (2022).

Zhu, T. et al. Immune microenvironment in osteosarcoma: components, therapeutic strategies and clinical applications. Front. Immunol. 13, 907550 (2022).

Piperno-Neumann, S. et al. Results of API-AI based regimen in osteosarcoma adult patients included in the French OS2006/Sarcome-09 study. Int. J. Cancer 146, 413–423 (2020).

Lamhamedi-Cherradi, S. E. et al. Transcriptional activators YAP/TAZ and AXL orchestrate dedifferentiation, cell fate, and metastasis in human osteosarcoma. Cancer Gene Ther. 28, 1325–1338 (2021).

Li, M., Wu, W., Deng, S., Shao, Z. & Jin, X. TRAIP modulates the IGFBP3/AKT pathway to enhance the invasion and proliferation of osteosarcoma by promoting KANK1 degradation. Cell Death Dis. 12, 767 (2021).

Liu, R., Hu, Y., Liu, T. & Wang, Y. Profiles of immune cell infiltration and immune-related genes in the tumor microenvironment of osteosarcoma cancer. BMC Cancer 21, 1345 (2021).

Wan, B. et al. Analysis of immune gene expression subtypes reveals osteosarcoma immune heterogeneity. J. Oncol. 2021, 6649412 (2021).

Bain, J. M. et al. Immune cells fold and damage fungal hyphae. Proc. Natl. Acad. Sci. USA 118, e2020484118 (2021).

Matsiko, A. Cancer immunotherapy making headway. Nat. Mater. 17, 472 (2018).

DeLucia, D. C. & Lee, J. K. Development of cancer immunotherapies. Cancer Treat. Res. 183, 1–48 (2022).

Starnes, C. O. Coley’s toxins. Nature 360, 23 (1992).

Zaaboub, R. et al. Nurselike cells sequester B cells in disorganized lymph nodes in chronic lymphocytic leukemia via alternative production of CCL21. Blood Adv. 6, 4691–4704 (2022).

Wu, B. et al. UBR5 promotes tumor immune evasion through enhancing IFN-γ-induced PDL1 transcription in triple-negative breast cancer. Theranostics 12, 5086–5102 (2022).

Zheng, B. et al. PD-1 axis expression in musculoskeletal tumors and antitumor effect of nivolumab in osteosarcoma model of humanized mouse. J. Hematol. Oncol. 11, 16 (2018).

Zhang, T. et al. Imaging-guided/improved diseases management for immune-strategies and beyond. Adv. Drug Deliv. Rev. 188, 114446 (2022).

Ali, S. et al. The European Medicines Agency Review of Kymriah (Tisagenlecleucel) for the treatment of acute lymphoblastic Leukemia and diffuse Large B-Cell lymphoma. Oncologist 25, e321–e327 (2020).

Wen, Y. et al. Immune checkpoints in osteosarcoma: recent advances and therapeutic potential. Cancer Lett. 547, 215887 (2022).

Brohl, A. S. et al. Immuno-transcriptomic profiling of extracranial pediatric solid malignancies. Cell Rep. 37, 110047 (2021).

Tian, L. R. et al. Nanodrug regulates lactic acid metabolism to reprogram the immunosuppressive tumor microenvironment for enhanced cancer immunotherapy. Biomater. Sci. 10, 3892–3900 (2022).

Liu, J., Li, L., Zhang, B. & Xu, Z. P. MnO(2)-shelled Doxorubicin/Curcumin nanoformulation for enhanced colorectal cancer chemo-immunotherapy. J. Colloid Interface Sci. 617, 315–325 (2022).

Han, Y., Wen, P., Li, J. & Kataoka, K. Targeted nanomedicine in cisplatin-based cancer therapeutics. J. Control Rel. 345, 709–720 (2022).

Rehman, S. et al. Unraveling enhanced brain delivery of paliperidone-loaded lipid nanoconstructs: pharmacokinetic, behavioral, biochemical, and histological aspects. Drug Deliv. 29, 1409–1422 (2022).

Tian, H. et al. Enhancing the therapeutic efficacy of nanoparticles for cancer treatment using versatile targeted strategies. J. Hematol. Oncol. 15, 132 (2022).

Chen, J. et al. Lipid nanoparticle-mediated lymph node-targeting delivery of mRNA cancer vaccine elicits robust CD8(+) T cell response. Proc. Natl. Acad. Sci. USA 119, e2207841119 (2022).

Singh, V. K. et al. CD44 receptor-targeted nanoparticles augment immunity against tuberculosis in mice. J. Control Rel. 349, 796–811 (2022).

Wang, T. et al. Biomimetic nanoparticles directly remodel immunosuppressive microenvironment for boosting glioblastoma immunotherapy. Bioact. Mater. 16, 418–432 (2022).

Li, S. et al. Advances of bacteria-based delivery systems for modulating tumor microenvironment. Adv. Drug Deliv. Rev. 188, 114444 (2022).

Wu, F. et al. Modulation of the tumor immune microenvironment by Bi(2) Te(3) -Au/Pd-based theranostic nanocatalysts enables efficient cancer therapy. Adv. Healthc. Mater. 11, e2200809 (2022).

Liu, K. et al. Photothermal-triggered immunogenic nanotherapeutics for optimizing osteosarcoma therapy by synergizing innate and adaptive immunity. Biomaterials 282, 121383 (2022).

Wang, H. et al. Subtype classification and prognosis signature construction of osteosarcoma based on cellular senescence-related genes. J. Oncol. 2022, 4421952 (2022).

Pierrevelcin, M. et al. Engineering Novel 3D models to recreate high-grade osteosarcoma and its immune and extracellular matrix microenvironment. Adv. Healthc. Mater. 11, e2200195 (2022).

Somaiah, N. et al. Durvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas: a single-centre phase 2 trial. Lancet Oncol. 23, 1156–1166 (2022).

Xie, X. et al. Remodeling tumor immunosuppressive microenvironment via a novel bioactive nanovaccines potentiates the efficacy of cancer immunotherapy. Bioact. Mater. 16, 107–119 (2022).

Wang, L. et al. Self-splittable transcytosis Nanoraspberry for NIR-II Photo-immunometabolic cancer therapy in deep tumor tissue. Adv Sci (Weinh) 9, e2204067 (2022).

Huang, X. et al. Dual-responsive nanosystem based on TGF-β blockade and immunogenic chemotherapy for effective chemoimmunotherapy. Drug Deliv. 29, 1358–1369 (2022).

Mi, H. et al. Quantitative spatial profiling of immune populations in pancreatic ductal adenocarcinoma reveals tumor microenvironment heterogeneity and prognostic biomarkers. Cancer 82, 4359–4372 (2022).

Li, M. et al. Tumor-derived exosomes deliver the tumor suppressor miR-3591-3p to induce M2 macrophage polarization and promote glioma progression. Oncogene 41, 4618–4632 (2022).

Kuo, C. L. et al. A Fc-VEGF chimeric fusion enhances PD-L1 immunotherapy via inducing immune reprogramming and infiltration in the immunosuppressive tumor microenvironment. Cancer Immunol. Immunother. 72, 351–369 (2022).

Poulin, L. F., Lasseaux, C. & Chamaillard, M. Understanding the cellular origin of the mononuclear phagocyte system sheds light on the myeloid postulate of immune paralysis in sepsis. Front. Immunol. 9, 823 (2018).

Yin, X. et al. Human Blood CD1c+ Dendritic cells encompass CD5high and CD5 low subsets that differ significantly in phenotype, gene expression, and functions. J. Immunol. 198, 1553–1564 (2017).

Collin, M. & Bigley, V. Human dendritic cell subsets: an update. Immunology 154, 3–20 (2018).

Talker, S. C. et al. Precise delineation and transcriptional characterization of bovine blood dendritic-cell and monocyte subsets. Front. Immunol. 9, 2505 (2018).

Zhou, Y. et al. Vaccine efficacy against primary and metastatic cancer with in vitro-generated CD103(+) conventional dendritic cells. J. Immunother. Cancer 8, e000474 (2020).

Meyer, M. A. et al. Breast and pancreatic cancer interrupt IRF8-dependent dendritic cell development to overcome immune surveillance. Nat. Commun. 9, 1250 (2018).

Makino, K. et al. Generation of cDC-like cells from human induced pluripotent stem cells via Notch signaling. J. Immunother. Cancer 10, e003827 (2022).

Inagaki, Y. et al. Dendritic and mast cell involvement in the inflammatory response to primary malignant bone tumours. Clin. Sarcoma Res. 6, 13 (2016).

Zhang, G. Z. et al. Development of a machine learning-based autophagy-related lncrna signature to improve prognosis prediction in osteosarcoma patients. Front Mol. Biosci. 8, 615084 (2021).

Le, T., Su, S., Kirshtein, A. & Shahriyari, L. Data-driven mathematical model of osteosarcoma. Cancers 13, 2367 (2021).

Kansara, M. et al. Infiltrating myeloid cells drive osteosarcoma progression via GRM4 regulation of IL23. Cancer Discov. 9, 1511–1519 (2019).

Jones, K. B. Dendritic cells drive Osteosarcomagenesis through newly identified oncogene and tumor suppressor. Cancer Discov. 9, 1484–1486 (2019).

Kawano, M., Itonaga, I., Iwasaki, T. & Tsumura, H. Enhancement of antitumor immunity by combining anti-cytotoxic T lymphocyte antigen-4 antibodies and cryotreated tumor lysate-pulsed dendritic cells in murine osteosarcoma. Oncol. Rep. 29, 1001–1006 (2013).

Zhou, Y. et al. Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma. Nat. Commun. 11, 6322 (2020).

Koirala, P. et al. Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma. Sci. Rep. 6, 30093 (2016).

Le, T., Su, S. & Shahriyari, L. Immune classification of osteosarcoma. Math. Biosci. Eng. 18, 1879–1897 (2021).

Lawir, D. F., Sikora, K., O’Meara, C. P., Schorpp, M. & Boehm, T. Pervasive changes of mRNA splicing in upf1-deficient zebrafish identify rpl10a as a regulator of T cell development. Proc. Natl. Acad. Sci. USA 117, 15799–15808 (2020).

Vogel, A., Kerndl, M., Schabbauer, G. & Sharif, O. Protocol to assess the tolerogenic properties of adoptively transferred dendritic cells during murine experimental autoimmune encephalomyelitis. STAR Protoc. 3, 101653 (2022).

Gan, X. et al. An anti-CTLA-4 heavy chain-only antibody with enhanced T(reg) depletion shows excellent preclinical efficacy and safety profile. Proc. Natl. Acad. Sci. USA 119, e2200879119 (2022).

Xia, S. et al. miR-150 promotes progressive T cell differentiation via inhibiting FOXP1 and RC3H1. Hum. Immunol. 83, 778–788 (2022).

Itahashi, K., Irie, T. & Nishikawa, H. Regulatory T-cell development in the tumor microenvironment. Eur. J. Immunol. 52, 1216–1227 (2022).

Liang, J. et al. Tumor-associated regulatory T cells in non-small-cell lung cancer: current advances and future perspectives. J. Immunol. Res. 2022, 4355386 (2022).

Schroeter, C. B. et al. Crosstalk of microorganisms and immune responses in autoimmune neuroinflammation: a focus on regulatory t cells. Front. Immunol. 12, 747143 (2021).

Yabe, H. et al. Prognostic significance of HLA class I expression in Ewing’s sarcoma family of tumors. J. Surg. Oncol. 103, 380–385 (2011).

Ligon, J. A. et al. Pathways of immune exclusion in metastatic osteosarcoma are associated with inferior patient outcomes. J. Immunother. Cancer 9, e001772 (2021).

Sundara, Y. T. et al. Increased PD-L1 and T-cell infiltration in the presence of HLA class I expression in metastatic high-grade osteosarcoma: a rationale for T-cell-based immunotherapy. Cancer Immunol. Immunother. 66, 119–128 (2017).

Tobita, S. et al. Successful continuous nivolumab therapy for metastatic non-small cell lung cancer after local treatment of oligometastatic lesions. Thorac. Cancer 11, 2357–2360 (2020).

Lavon, I., Heli, C., Brill, L., Charbit, H. & Vaknin-Dembinsky, A. Blood levels of co-inhibitory-receptors: a biomarker of disease prognosis in multiple sclerosis. Front. Immunol. 10, 835 (2019).

Su, M., Huang, C. X. & Dai, A. P. Immune checkpoint inhibitors: therapeutic tools for breast cancer. Asian Pac. J. Cancer Prev. 17, 905–910 (2016).

Han, Q., Shi, H. & Liu, F. CD163(+) M2-type tumor-associated macrophage support the suppression of tumor-infiltrating T cells in osteosarcoma. Int Immunopharmacol. 34, 101–106 (2016).

Matsuo, T. et al. Extraskeletal osteosarcoma with partial spontaneous regression. Anticancer Res. 29, 5197–5201 (2009).

Maskalenko, N. A., Zhigarev, D. & Campbell, K. S. Harnessing natural killer cells for cancer immunotherapy: dispatching the first responders. Nat. Rev. Drug Disco. 21, 559–577 (2022).

Croft, C. A. et al. Notch, RORC and IL-23 signals cooperate to promote multi-lineage human innate lymphoid cell differentiation. Nat. Commun. 13, 4344 (2022).

Le, H., Spearman, P., Waggoner, S. N. & Singh, K. Ebola virus protein VP40 stimulates IL-12- and IL-18-dependent activation of human natural killer cells. JCI Insight 7, e158902 (2022).

Pende, D. et al. Killer Ig-like Receptors (KIRs): Their role in NK cell modulation and developments leading to their clinical exploitation. Front. Immunol. 10, 1179 (2019).

Zheng, G., Jia, L. & Yang, A. G. Roles of HLA-G/KIR2DL4 in breast cancer immune microenvironment. Front. Immunol. 13, 791975 (2022).

D’Amico, S. et al. ERAP1 controls the interaction of the inhibitory receptor KIR3DL1 with HLA-B51: 01 by affecting natural killer cell function. Front. Immunol. 12, 778103 (2021).

Boudreau, J. E. & Hsu, K. C. Natural killer cell education and the response to infection and cancer therapy: stay tuned. Trends Immunol. 39, 222–239 (2018).

Borrego, F. et al. Structure and function of major histocompatibility complex (MHC) class I specific receptors expressed on human natural killer (NK) cells. Mol. Immunol. 38, 637–660 (2002).

Barrow, A. D., Martin, C. J. & Colonna, M. The natural cytotoxicity receptors in health and disease. Front. Immunol. 10, 909 (2019).

Lee, G. H. et al. Clinical impact of natural killer Group 2D receptor expression and that of its ligand in ovarian carcinomas: a retrospective study. Yonsei Med. J. 62, 288–297 (2021).

Kegasawa, T. et al. Soluble UL16-binding protein 2 is associated with a poor prognosis in pancreatic cancer patients. Biochem. Biophys. Res. Commun. 517, 84–88 (2019).

Tsertsvadze, T., Mitskevich, N., Bilanishvili, A., Girdaladze, D. & Porakishvili, N. Phagocytosis and expression of FCg-receptors and CD180 on monocytes in chronic lymphocytic leukemia. Georgian Med. News 88–93 (2017).

Sivori, S. et al. Human NK cells: surface receptors, inhibitory checkpoints, and translational applications. Cell Mol. Immunol. 16, 430–441 (2019).

Souza-Fonseca-Guimaraes, F., Cursons, J. & Huntington, N. D. The emergence of natural killer cells as a major target in cancer immunotherapy. Trends Immunol. 40, 142–158 (2019).

Ogiwara, Y. et al. Blocking FSTL1 boosts NK immunity in treatment of osteosarcoma. Cancer Lett. 537, 215690 (2022).

Razmara, A. M. et al. Natural killer and T cell infiltration in canine osteosarcoma: clinical implications and translational relevance. Front. Vet. Sci. 8, 771737 (2021).

Lim, K. S., Mimura, K., Kua, L. F., Shiraishi, K. & Kono, K. Implication of highly cytotoxic natural killer cells for esophageal squamous cell carcinoma treatment. J. Immunother. 41, 261–273 (2018).

Baek, H. J. et al. Ex vivo expansion of natural killer cells using cryopreserved irradiated feeder cells. Anticancer Res. 33, 2011–2019 (2013).

Cho, D. et al. Cytotoxicity of activated natural killer cells against pediatric solid tumors. Clin. Cancer Res. 16, 3901–3909 (2010).

Fernández, L. et al. Activated and expanded natural killer cells target osteosarcoma tumor initiating cells in an NKG2D-NKG2DL dependent manner. Cancer Lett. 368, 54–63 (2015).

Zhu, S. et al. The narrow-spectrum HDAC inhibitor entinostat enhances NKG2D expression without NK cell toxicity, leading to enhanced recognition of cancer cells. Pharm. Res. 32, 779–792 (2015).

Otegbeye, F. et al. Natural killer cell alloreactivity predicted by killer cell immunoglobulin-like receptor ligand mismatch does not impact engraftment in umbilical cord blood and haploidentical stem cell transplantation. Transpl. Cell Ther. 28, 483.e481–483.e487 (2022).

Zhang, Y. et al. Mesenchymal stem cells enhance the impact of KIR receptor-ligand mismatching on acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia but not in those with acute lymphocytic leukemia. Hematol. Oncol. 39, 380–389 (2021).

Arvanitakis, K., Koletsa, T., Mitroulis, I. & Germanidis, G. Tumor-associated macrophages in hepatocellular carcinoma pathogenesis, prognosis and therapy. Cancers 14, 226 (2022).

Izumi, Y. et al. An antibody-drug conjugate that selectively targets human monocyte progenitors for anti-cancer therapy. Front. Immunol. 12, 618081 (2021).

Wu, X. Q. et al. Increased expression of tribbles homolog 3 predicts poor prognosis and correlates with tumor immunity in clear cell renal cell carcinoma: a bioinformatics study. Bioengineered 13, 14000–14012 (2022).

Kelleher, F. C. & O’Sullivan, H. Monocytes, macrophages, and osteoclasts in osteosarcoma. J. Adolesc. Young-. Adult Oncol. 6, 396–405 (2017).

Italiani, P. & Boraschi, D. From monocytes to M1/M2 macrophages: phenotypical vs. functional differentiation. Front. Immunol. 5, 514 (2014).

Brifault, C., Gilder, A. S., Laudati, E., Banki, M. & Gonias, S. L. Shedding of membrane-associated LDL receptor-related protein-1 from microglia amplifies and sustains neuroinflammation. J. Biol. Chem. 292, 18699–18712 (2017).

Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).

Shapouri-Moghaddam, A. et al. Macrophage plasticity, polarization, and function in health and disease. J. Cell Physiol. 233, 6425–6440 (2018).

Komohara, Y., Fujiwara, Y., Ohnishi, K. & Takeya, M. Tumor-associated macrophages: Potential therapeutic targets for anti-cancer therapy. Adv. Drug Deliv. Rev. 99, 180–185 (2016).

Huang, Q. et al. The role of tumor-associated macrophages in osteosarcoma progression - therapeutic implications. Cell Oncol. 44, 525–539 (2021).

Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).

Kielbassa, K., Vegna, S., Ramirez, C. & Akkari, L. Understanding the origin and diversity of macrophages to tailor their targeting in solid cancers. Front. Immunol. 10, 2215 (2019).

Dudzinski, S. O. et al. Leptin augments antitumor immunity in obesity by repolarizing tumor-associated macrophages. J. Immunol. 207, 3122–3130 (2021).

Ahirwar, D. K. et al. Slit2 inhibits breast cancer metastasis by activating M1-like phagocytic and antifibrotic macrophages. Cancer Res. 81, 5255–5267 (2021).

Szulc-Kielbik, I. & Kielbik, M. Tumor-associated macrophages: reasons to be cheerful, reasons to be fearful. Exp. Suppl. 113, 107–140 (2022).

Wang, X. et al. HMGA2 facilitates colorectal cancer progression via STAT3-mediated tumor-associated macrophage recruitment. Theranostics 12, 963–975 (2022).

Deng, C. et al. Reprograming the tumor immunologic microenvironment using neoadjuvant chemotherapy in osteosarcoma. Cancer Sci. 111, 1899–1909 (2020).

Shao, X. J. et al. Inhibition of M2-like macrophages by all-trans retinoic acid prevents cancer initiation and stemness in osteosarcoma cells. Acta Pharm. Sin. 40, 1343–1350 (2019).

Cassetta, L. & Pollard, J. W. Targeting macrophages: therapeutic approaches in cancer. Nat. Rev. Drug Discov. 17, 887–904 (2018).

Jakab, M., Rostalski, T., Lee, K. H., Mogler, C. & Augustin, H. G. Tie2 receptor in tumor-infiltrating macrophages is dispensable for tumor angiogenesis and tumor relapse after chemotherapy. Cancer Res. 82, 1353–1364 (2022).

Zhang, J., Zhou, X. & Hao, H. Macrophage phenotype-switching in cancer. Eur. J. Pharm. 931, 175229 (2022).

Sun, Q. et al. Lenvatinib for effectively treating antiangiogenic drug-resistant nasopharyngeal carcinoma. Cell Death Dis. 13, 724 (2022).

Hang, X. et al. BCL-2 isoform β promotes angiogenesis by TRiC-mediated upregulation of VEGF-A in lymphoma. Oncogene 41, 3655–3663 (2022).

Huang, C. Y. et al. Fluoroquinolones suppress TGF-β and PMA-induced MMP-9 production in cancer cells: implications in repurposing quinolone antibiotics for cancer treatment. Int. J. Mol. Sci. 22, 11602 (2021).

Patel, S. S. et al. The microenvironmental niche in classic Hodgkin lymphoma is enriched for CTLA-4-positive T cells that are PD-1-negative. Blood 134, 2059–2069 (2019).

Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).

Zhang, P. et al. Macrophages promote coal tar pitch extract-induced tumorigenesis of BEAS-2B cells and tumor metastasis in nude mice mediated by AP-1. Asian Pac. J. Cancer Prev. 15, 4871–4876 (2014).

Han, Y. et al. Tumor-associated macrophages promote lung metastasis and induce epithelial-mesenchymal transition in osteosarcoma by activating the COX-2/STAT3 axis. Cancer Lett. 440-441, 116–125 (2019).

Etzerodt, A. et al. Specific targeting of CD163(+) TAMs mobilizes inflammatory monocytes and promotes T cell-mediated tumor regression. J. Exp. Med. 216, 2394–2411 (2019).

Yamaguchi, Y. et al. PD-L1 blockade restores CAR T cell activity through IFN-γ-regulation of CD163+ M2 macrophages. J. Immunother. Cancer 10, e004400 (2022).

Eruslanov, E. B., Singhal, S. & Albelda, S. M. Mouse versus human neutrophils in cancer: a major knowledge gap. Trends Cancer 3, 149–160 (2017).

Mestas, J. & Hughes, C. C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).

Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).

Yang, S., Wu, C., Wang, L., Shan, D. & Chen, B. Pretreatment inflammatory indexes as prognostic predictors for survival in osteosarcoma patients. Int. J. Clin. Exp. Pathol. 13, 515–524 (2020).

Liu, B. et al. Prognostic value of inflammation-based scores in patients with osteosarcoma. Sci. Rep. 6, 39862 (2016).

Xia, W. K. et al. Prognostic performance of pre-treatment NLR and PLR in patients suffering from osteosarcoma. World J. Surg. Oncol. 14, 127 (2016).

Vasquez, L. et al. Pretreatment Neutrophil-to-Lymphocyte ratio and lymphocyte recovery: independent prognostic factors for survival in pediatric sarcomas. J. Pediatr. Hematol. Oncol. 39, 538–546 (2017).

Yapar, A. et al. Diagnostic and prognostic role of neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and lymphocyte/monocyte ratio in patients with osteosarcoma. Jt Dis. Relat. Surg. 32, 489–496 (2021).

Wu, L., Saxena, S., Awaji, M. & Singh, R. K. Tumor-associated neutrophils in cancer: going pro. Cancers 11, 564 (2019).

Filep, J. G. Targeting neutrophils for promoting the resolution of inflammation. Front. Immunol. 13, 866747 (2022).

Silvestre-Roig, C., Hidalgo, A. & Soehnlein, O. Neutrophil heterogeneity: implications for homeostasis and pathogenesis. Blood 127, 2173–2181 (2016).

Pillay, J. et al. In vivo labeling with 2H₂O reveals a human neutrophil lifespan of 5.4 days. Blood 116, 625–627 (2010).

Akgul, C., Moulding, D. A. & Edwards, S. W. Molecular control of neutrophil apoptosis. FEBS Lett. 487, 318–322 (2001).

Carestia, A., Kaufman, T. & Schattner, M. Platelets: New bricks in the building of neutrophil extracellular traps. Front. Immunol. 7, 271 (2016).

Papayannopoulos, V. Neutrophil extracellular traps in immunity and disease. Nat. Rev. Immunol. 18, 134–147 (2018).

Leshner, M. et al. PAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structures. Front. Immunol. 3, 307 (2012).

Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).

Gabrilovich, D. I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).

Bronte, V. et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 7, 12150 (2016).

Mishalian, I. et al. Tumor-associated neutrophils (TAN) develop pro-tumorigenic properties during tumor progression. Cancer Immunol. Immunother. 62, 1745–1756 (2013).

Sun, R. et al. Neutrophils with protumor potential could efficiently suppress tumor growth after cytokine priming and in presence of normal NK cells. Oncotarget 5, 12621–12634 (2014).

Coffelt, S. B., Wellenstein, M. D. & de Visser, K. E. Neutrophils in cancer: neutral no more. Nat. Rev. Cancer 16, 431–446 (2016).

Jaillon, S. et al. Neutrophil diversity, and plasticity in tumour progression and therapy. Nat. Rev. Cancer 20, 485–503 (2020).

Shaul, M. E. & Fridlender, Z. G. Tumour-associated neutrophils in patients with cancer. Nat. Rev. Clin. Oncol. 16, 601–620 (2019).

Powell, D. R. & Huttenlocher, A. Neutrophils in the Tumor Microenvironment. Trends Immunol. 37, 41–52 (2016).

Yang, B. et al. Identification of prognostic biomarkers associated with metastasis and immune infiltration in osteosarcoma. Oncol. Lett. 21, 180 (2021).

Furumaya, C., Martinez-Sanz, P., Bouti, P., Kuijpers, T. W. & Matlung, H. L. Plasticity in Pro- and anti-tumor activity of neutrophils: shifting the balance. Front. Immunol. 11, 2100 (2020).

Zhang, X. et al. Neutrophils in cancer development and progression: Roles, mechanisms, and implications (Review). Int. J. Oncol. 49, 857–867 (2016).

Zhang, C. et al. Neutrophils correlate with hypoxia microenvironment and promote progression of non-small-cell lung cancer. Bioengineered 12, 8872–8884 (2021).

Fu, Y. et al. Development and validation of a hypoxia-associated prognostic signature related to osteosarcoma metastasis and immune infiltration. Front. Cell Dev. Biol. 9, 633607 (2021).

Wang, Y. et al. CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment. Bioact. Mater. 17, 147–161 (2022).

Wang, W. et al. Engineering micro oxygen factories to slow tumour progression via hyperoxic microenvironments. Nat. Commun. 13, 4495 (2022).

Dou, A. & Fang, J. Heterogeneous myeloid cells in tumors. Cancers 13, 3772 (2021).

De Vlaeminck, Y., González-Rascón, A., Goyvaerts, C. & Breckpot, K. Cancer-associated myeloid regulatory cells. Front Immunol. 7, 113 (2016).

Ling, Z., Yang, C., Tan, J., Dou, C. & Chen, Y. Beyond immunosuppressive effects: dual roles of myeloid-derived suppressor cells in bone-related diseases. Cell Mol. Life Sci. 78, 7161–7183 (2021).

Horlad, H. et al. Corosolic acid impairs tumor development and lung metastasis by inhibiting the immunosuppressive activity of myeloid-derived suppressor cells. Mol. Nutr. Food Res. 57, 1046–1054 (2013).

Wu, S. Y. & Chiang, C. S. Distinct role of CD11b(+)Ly6G(-)Ly6C(-) Myeloid-derived cells on the progression of the primary tumor and therapy-associated recurrent brain tumor. Cells 9, 51 (2019).

Ribechini, E., Greifenberg, V., Sandwick, S. & Lutz, M. B. Subsets, expansion and activation of myeloid-derived suppressor cells. Med. Microbiol Immunol. 199, 273–281 (2010).

Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).

Bottomley, M. J., Harden, P. N., Wood, K. J., Hester, J. & Issa, F. Dampened Inflammatory signalling and myeloid-derived suppressor-like cell accumulation reduces circulating monocytic HLA-DR density and may associate with malignancy risk in long-term renal transplant recipients. Front. Immunol. 13, 901273 (2022).

Mukherjee, S. et al. IL-6 dependent expansion of inflammatory MDSCs (CD11b+ Gr-1+) promote Th-17 mediated immune response during experimental cerebral malaria. Cytokine 155, 155910 (2022).

Scirocchi, F. et al. Immune effects of CDK4/6 inhibitors in patients with HR(+)/HER2(-) metastatic breast cancer: Relief from immunosuppression is associated with clinical response. EBioMedicine 79, 104010 (2022).

Joshi, S. & Sharabi, A. Targeting myeloid-derived suppressor cells to enhance natural killer cell-based immunotherapy. Pharm. Ther. 235, 108114 (2022).

Fionda, C., Abruzzese, M. P., Santoni, A. & Cippitelli, M. Immunoregulatory and effector activities of nitric oxide and reactive nitrogen species in cancer. Curr. Med. Chem. 23, 2618–2636 (2016).

Sasidharan Nair, V., Saleh, R., Toor, S. M., Alajez, N. M. & Elkord, E. Transcriptomic analyses of myeloid-derived suppressor cell subsets in the circulation of colorectal cancer patients. Front. Oncol. 10, 1530 (2020).

Porta, C. et al. Tumor-derived Prostaglandin E2 promotes p50 NF-κB-dependent differentiation of monocytic MDSCs. Cancer Res. 80, 2874–2888 (2020).

Xin, B. et al. Enhancing the therapeutic efficacy of programmed death ligand 1 antibody for metastasized liver cancer by overcoming hepatic immunotolerance in mice. Hepatology 76, 630–645 (2022).

Zhang, X. et al. CD147 mediates epidermal malignant transformation through the RSK2/AP-1 pathway. J. Exp. Clin. Cancer Res. 41, 246 (2022).

Rodríguez, P. C. & Ochoa, A. C. Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol. Rev. 222, 180–191 (2008).

Yang, Y., Li, C., Liu, T., Dai, X. & Bazhin, A. V. Myeloid-derived suppressor cells in tumors: from mechanisms to antigen specificity and microenvironmental regulation. Front. Immunol. 11, 1371 (2020).

Gabrilovich, D. I. Myeloid-derived suppressor cells. Cancer Immunol. Res. 5, 3–8 (2017).

Sevko, A. & Umansky, V. Myeloid-derived suppressor cells interact with tumors in terms of myelopoiesis, tumorigenesis and immunosuppression: thick as thieves. J. Cancer 4, 3–11 (2013).

Marvel, D. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J. Clin. Invest. 125, 3356–3364 (2015).

Wang, N. et al. 3D hESC exosomes enriched with miR-6766-3p ameliorates liver fibrosis by attenuating activated stellate cells through targeting the TGFβRII-SMADS pathway. J. Nanobiotechnology 19, 437 (2021).

Liu, H., Sun, X., Gong, X. & Wang, G. Human umbilical cord mesenchymal stem cells derived exosomes exert antiapoptosis effect via activating PI3K/Akt/mTOR pathway on H9C2 cells. J. Cell Biochem. 120, 14455–14464 (2019).

Jiao, Y. et al. Tumor cell-derived extracellular vesicles for breast cancer specific delivery of therapeutic P53. J. Control Release 349, 606–616 (2022).

De Martino, V. et al. Extracellular vesicles in osteosarcoma: antagonists or therapeutic agents? Int. J. Mol. Sci. 22, 12586 (2021).

Hareendran, S., Yang, X., Sharma, V. K. & Loh, Y. P. Carboxypeptidase E and its splice variants: Key regulators of growth and metastasis in multiple cancer types. Cancer Lett. 548, 215882 (2022).

Zhang, Y. et al. H3K27 acetylation activated-COL6A1 promotes osteosarcoma lung metastasis by repressing STAT1 and activating pulmonary cancer-associated fibroblasts. Theranostics 11, 1473–1492 (2021).

Du, M. et al. Genome-wide CRISPR screen identified Rad18 as a determinant of doxorubicin sensitivity in osteosarcoma. J. Exp. Clin. Cancer Res. 41, 154 (2022).

Cappariello, A. & Rucci, N. Tumour-derived Extracellular Vesicles (EVs): A dangerous “Message in A Bottle” for Bone. Int. J. Mol. Sci. 20, 4805 (2019).

Greening, D. W., Gopal, S. K., Xu, R., Simpson, R. J. & Chen, W. Exosomes and their roles in immune regulation and cancer. Semin Cell Dev. Biol. 40, 72–81 (2015).

Troyer, R. M. et al. Exosomes from Osteosarcoma and normal osteoblast differ in proteomic cargo and immunomodulatory effects on T cells. Exp. Cell Res. 358, 369–376 (2017).

Wang, J. et al. Exosomal PD-L1 and N-cadherin predict pulmonary metastasis progression for osteosarcoma patients. J. Nanobiotechnology 18, 151 (2020).

Isla Larrain, M. T. et al. IDO is highly expressed in breast cancer and breast cancer-derived circulating microvesicles and associated to aggressive types of tumors by in silico analysis. Tumour Biol. 35, 6511–6519 (2014).

Wang, S., Ma, F., Feng, Y., Liu, T. & He, S. Role of exosomal miR‑21 in the tumor microenvironment and osteosarcoma tumorigenesis and progression (Review). Int J. Oncol. 56, 1055–1063 (2020).

Schiavone, K., Garnier, D., Heymann, M. F. & Heymann, D. The heterogeneity of Osteosarcoma: The role played by cancer stem cells. Adv. Exp. Med. Biol. 1139, 187–200 (2019).

Xu, A. et al. Cell Differentiation trajectory-associated molecular classification of Osteosarcoma. Genes 12, 1685 (2021).

Sarhadi, V. K., Daddali, R. & Seppänen-Kaijansinkko, R. Mesenchymal stem cells and extracellular vesicles in osteosarcoma pathogenesis and therapy. Int. J. Mol. Sci. 22, 11035 (2021).

Sole, A. et al. Unraveling Ewing Sarcoma Tumorigenesis originating from patient-derived mesenchymal stem cells. Cancer Res. 81, 4994–5006 (2021).

Mannerström, B. et al. Epigenetic alterations in mesenchymal stem cells by osteosarcoma-derived extracellular vesicles. Epigenetics 14, 352–364 (2019).

Wang, J. Y. et al. Generation of Osteosarcomas from a combination of Rb silencing and c-Myc overexpression in human mesenchymal stem cells. Stem Cells Transl. Med. 6, 512–526 (2017).

Chang, X., Ma, Z., Zhu, G., Lu, Y. & Yang, J. New perspective into mesenchymal stem cells: Molecular mechanisms regulating osteosarcoma. J. Bone Oncol. 29, 100372 (2021).

Sun, Z., Wang, S. & Zhao, R. C. The roles of mesenchymal stem cells in tumor inflammatory microenvironment. J. Hematol. Oncol. 7, 14 (2014).

Kawano, M., Tanaka, K., Itonaga, I., Iwasaki, T. & Tsumura, H. Interaction between human osteosarcoma and mesenchymal stem cells via an interleukin-8 signaling loop in the tumor microenvironment. Cell Commun. Signal 16, 13 (2018).

Du, L. et al. CXCR1/Akt signaling activation induced by mesenchymal stem cell-derived IL-8 promotes osteosarcoma cell anoikis resistance and pulmonary metastasis. Cell Death Dis. 9, 714 (2018).

Pelagalli, A., Nardelli, A., Fontanella, R. & Zannetti, A. Inhibition of AQP1 Hampers Osteosarcoma and Hepatocellular Carcinoma progression mediated by bone marrow-derived mesenchymal stem cells. Int. J. Mol. Sci. 17, 1102 (2016).

Deng, Q. et al. Activation of hedgehog signaling in mesenchymal stem cells induces cartilage and bone tumor formation via Wnt/β-Catenin. Elife 8, e50208 (2019).

Pietrovito, L. et al. Bone marrow-derived mesenchymal stem cells promote invasiveness and transendothelial migration of osteosarcoma cells via a mesenchymal to amoeboid transition. Mol. Oncol. 12, 659–676 (2018).

Baglio, S. R. et al. Blocking tumor-educated MSC Paracrine activity halts Osteosarcoma progression. Clin. Cancer Res. 23, 3721–3733 (2017).

Lin, L. et al. Conditioned medium of the osteosarcoma cell line U2OS induces hBMSCs to exhibit characteristics of carcinoma-associated fibroblasts via activation of IL-6/STAT3 signalling. J. Biochem. 168, 265–271 (2020).

Chang, A. I., Schwertschkow, A. H., Nolta, J. A. & Wu, J. Involvement of mesenchymal stem cells in cancer progression and metastases. Curr. Cancer Drug Targets 15, 88–98 (2015).

Lagerweij, T., Pérez-Lanzón, M. & Baglio, S. R. A preclinical mouse model of osteosarcoma to define the extracellular vesicle-mediated communication between tumor and mesenchymal stem cells. J. Vis. Exp 135, 56932 (2018).

Zhang, Q. et al. Exosomes originating from MSCs stimulated with TGF-β and IFN-γ promote Treg differentiation. J. Cell Physiol. 233, 6832–6840 (2018).

Khare, D. et al. Mesenchymal stromal cell-derived exosomes affect mRNA expression and function of B-Lymphocytes. Front. Immunol. 9, 3053 (2018).

Li, W. et al. Gastric cancer-derived mesenchymal stromal cells trigger M2 macrophage polarization that promotes metastasis and EMT in gastric cancer. Cell Death Dis. 10, 918 (2019).

Jia, X. H. et al. Activation of mesenchymal stem cells by macrophages promotes tumor progression through immune suppressive effects. Oncotarget 7, 20934–20944 (2016).

Mardpour, S. et al. Interaction between mesenchymal stromal cell-derived extracellular vesicles and immune cells by distinct protein content. J. Cell Physiol. 234, 8249–8258 (2019).

Chang, L., Asatrian, G., Dry, S. M. & James, A. W. Circulating tumor cells in sarcomas: a brief review. Med. Oncol. 32, 430 (2015).

Wu, Z. J., Tan, J. C., Qin, X., Liu, B. & Yuan, Z. C. Significance of circulating tumor cells in osteosarcoma patients treated by neoadjuvant chemotherapy and surgery. Cancer Manag Res. 10, 3333–3339 (2018).

Cortini, M. et al. Exploring metabolic adaptations to the acidic microenvironment of Osteosarcoma cells unveils Sphingosine 1-Phosphate as a valuable therapeutic target. Cancers 13, 311 (2021).

Zhang, Y. et al. Interleukin-6 suppression reduces tumour self-seeding by circulating tumour cells in a human osteosarcoma nude mouse model. Oncotarget 7, 446–458 (2016).

Liu, T. et al. Self-seeding circulating tumor cells promote the proliferation and metastasis of human osteosarcoma by upregulating interleukin-8. Cell Death Dis. 10, 575 (2019).

Sun, Q. et al. Nanomedicine and macroscale materials in immuno-oncology. Chem. Soc. Rev. 48, 351–381 (2019).

Preusser, M., Berghoff, A. S., Thallinger, C. & Zielinski, C. C. Cancer immune cycle: a video introduction to the interaction between cancer and the immune system. ESMO Open 1, e000056 (2016).

Kim, K. S., Youn, Y. S. & Bae, Y. H. Immune-triggered cancer treatment by intestinal lymphatic delivery of docetaxel-loaded nanoparticle. J. Control Release 311-312, 85–95 (2019).

Meng, Z. et al. Tumor immunotherapy boosted by R837 nanocrystals through combining chemotherapy and mild hyperthermia. J. Control Release 350, 841–856 (2022).

Yang, J. & Zhang, C. Regulation of cancer-immunity cycle and tumor microenvironment by nanobiomaterials to enhance tumor immunotherapy. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol 12, e1612 (2020).

Galiana, I. et al. Preclinical antitumor efficacy of senescence-inducing chemotherapy combined with a nanoSenolytic. J. Control Rel. 323, 624–634 (2020).

Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).

Anfray, C., Ummarino, A., Andón, F. T. & Allavena, P. Current strategies to target tumor-associated-macrophages to improve anti-tumor immune responses. Cells 9, 46 (2019).

van Dalen, F. J., van Stevendaal, M., Fennemann, F. L., Verdoes, M. & Ilina, O. Molecular repolarisation of tumour-associated macrophages. Molecules 24, 9 (2018).

Shime, H. et al. Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors. Proc. Natl. Acad. Sci. USA 109, 2066–2071 (2012).

Vidyarthi, A. et al. TLR-3 stimulation Skews M2 macrophages to M1 through IFN-αβ signaling and restricts tumor progression. Front. Immunol. 9, 1650 (2018).

Helleberg Madsen, N., Schnack Nielsen, B., Larsen, J. & Gad, M. In vitro 2D and 3D cancer models to evaluate compounds that modulate macrophage polarization. Cell Immunol. 378, 104574 (2022).

Ubil, E. et al. Tumor-secreted Pros1 inhibits macrophage M1 polarization to reduce antitumor immune response. J. Clin. Invest. 128, 2356–2369 (2018).

Pahl, J. H. et al. Macrophages inhibit human osteosarcoma cell growth after activation with the bacterial cell wall derivative liposomal muramyl tripeptide in combination with interferon-γ. J. Exp. Clin. Cancer Res. 33, 27 (2014).

Wang, J. C. et al. Metformin’s antitumour and anti-angiogenic activities are mediated by skewing macrophage polarization. J. Cell Mol. Med. 22, 3825–3836 (2018).

Uehara, T. et al. Metformin induces CD11b+-cell-mediated growth inhibition of an osteosarcoma: implications for metabolic reprogramming of myeloid cells and anti-tumor effects. Int. Immunol. 31, 187–198 (2019).

Maloney, C. et al. Gefitinib inhibits invasion and metastasis of Osteosarcoma via inhibition of macrophage receptor interacting Serine-Threonine Kinase 2. Mol. Cancer Ther. 19, 1340–1350 (2020).

Yang, M. et al. MYLK4 promotes tumor progression through the activation of epidermal growth factor receptor signaling in osteosarcoma. J. Exp. Clin. Cancer Res. 40, 166 (2021).

Wang, S. et al. Stattic sensitizes osteosarcoma cells to epidermal growth factor receptor inhibitors via blocking the interleukin 6-induced STAT3 pathway. Acta Biochim. Biophys. Sin. 53, 1670–1680 (2021).

Kallis, M. P. et al. Pharmacological prevention of surgery-accelerated metastasis in an animal model of osteosarcoma. J. Transl. Med. 18, 183 (2020).

Nohara, T. et al. Antitumor allium sulfides. Chem. Pharm. Bull. 65, 209–217 (2017).

Nohara, T. et al. Thiolane-type sulfides from garlic, onion, and Welsh onion. J. Nat. Med. 75, 741–751 (2021).

Fujiwara, Y., Takeya, M. & Komohara, Y. A novel strategy for inducing the antitumor effects of triterpenoid compounds: blocking the protumoral functions of tumor-associated macrophages via STAT3 inhibition. Biomed. Res. Int. 2014, 348539 (2014).

Chen, X. et al. Oleanolic acid inhibits osteosarcoma cell proliferation and invasion by suppressing the SOX9/Wnt1 signaling pathway. Exp. Ther. Med. 21, 443 (2021).

Kimura, Y. & Sumiyoshi, M. Anti-tumor and anti-metastatic actions of wogonin isolated from Scutellaria baicalensis roots through anti-lymphangiogenesis. Phytomedicine 20, 328–336 (2013).

Kimura, Y. & Sumiyoshi, M. Antitumor and antimetastatic actions of dihydroxycoumarins (esculetin or fraxetin) through the inhibition of M2 macrophage differentiation in tumor-associated macrophages and/or G1 arrest in tumor cells. Eur. J. Pharm. 746, 115–125 (2015).

Sumiyoshi, M., Taniguchi, M., Baba, K. & Kimura, Y. Antitumor and antimetastatic actions of xanthoangelol and 4-hydroxyderricin isolated from Angelica Keiskei roots through the inhibited activation and differentiation of M2 macrophages. Phytomedicine 22, 759–767 (2015).

Kimura, Y. & Sumiyoshi, M. Resveratrol prevents tumor growth and metastasis by inhibiting Lymphangiogenesis and M2 macrophage activation and differentiation in tumor-associated macrophages. Nutr. Cancer 68, 667–678 (2016).

Kimura, Y., Sumiyoshi, M. & Baba, K. Antitumor and antimetastatic activity of synthetic hydroxystilbenes through inhibition of lymphangiogenesis and M2 macrophage differentiation of tumor-associated macrophages. Anticancer Res. 36, 137–148 (2016).

Caldeira, J. C., Perrine, M., Pericle, F. & Cavallo, F. Virus-like particles as an immunogenic platform for cancer vaccines. Viruses 12, 488 (2020).

Ying, K. et al. Macrophage membrane-biomimetic adhesive polycaprolactone nanocamptothecin for improving cancer-targeting efficiency and impairing metastasis. Bioact. Mater. 20, 449–462 (2023).

Sun, L. et al. Long-term effect of mobile phone-based education and influencing factors of willingness to receive HPV vaccination among female freshmen in Shanxi Province, China. Hum. Vaccin Immunother. 18, 2051990 (2022).

Marcove, R. C., Miké, V., Huvos, A. G., Southam, C. M. & Levin, A. G. Vaccine trials for osteogenic sarcoma. A preliminary report. CA Cancer J. Clin. 23, 74–80 (1973).

Wang, Z. et al. Innate immune cells: a potential and promising cell population for treating Osteosarcoma. Front. Immunol. 10, 1114 (2019).

Tsukahara, T. et al. The future of immunotherapy for sarcoma. Expert Opin. Biol. Ther. 16, 1049–1057 (2016).

Shemesh, C. S. et al. Personalized cancer vaccines: clinical landscape, challenges, and opportunities. Mol. Ther. 29, 555–570 (2021).

van der Bruggen, P. et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254, 1643–1647 (1991).

Mason, N. J. et al. Immunotherapy with a HER2-targeting Listeria Induces HER2-specific immunity and demonstrates potential therapeutic effects in a Phase I trial in Canine Osteosarcoma. Clin. Cancer Res. 22, 4380–4390 (2016).

Pritchard-Jones, K. et al. Immune responses to the 105AD7 human anti-idiotypic vaccine after intensive chemotherapy, for osteosarcoma. Br. J. Cancer 92, 1358–1365 (2005).

Ullenhag, G. J. et al. T-cell responses in osteosarcoma patients vaccinated with an anti-idiotypic antibody, 105AD7, mimicking CD55. Clin. Immunol. 128, 148–154 (2008).

Li, D., Toji, S., Watanabe, K., Torigoe, T. & Tsukahara, T. Identification of novel human leukocyte antigen-A*11: 01-restricted cytotoxic T-lymphocyte epitopes derived from osteosarcoma antigen papillomavirus binding factor. Cancer Sci. 110, 1156–1168 (2019).

Tsukahara, T. et al. Specific targeting of a naturally presented osteosarcoma antigen, papillomavirus binding factor peptide, using an artificial monoclonal antibody. J. Biol. Chem. 289, 22035–22047 (2014).

Holland, D. et al. Activation of the enhancer of Zeste homologue 2 gene by the human papillomavirus E7 oncoprotein. Cancer Res. 68, 9964–9972 (2008).

Peng, W., Huang, X. & Yang, D. EWS/FLI-l peptide-pulsed dendritic cells induces the antitumor immunity in a murine Ewing’s sarcoma cell model. Int. Immunopharmacol. 21, 336–341 (2014).

Tsuda, N. et al. Expression of a newly defined tumor-rejection antigen SART3 in musculoskeletal tumors and induction of HLA class I-restricted cytotoxic T lymphocytes by SART3-derived peptides. J. Orthop. Res. 19, 346–351 (2001).

Tsukahara, T. et al. Identification of human autologous cytotoxic T-lymphocyte-defined osteosarcoma gene that encodes a transcriptional regulator, papillomavirus binding factor. Cancer Res. 64, 5442–5448 (2004).

He, F. et al. GATA3/long noncoding RNA MHC-R regulates the immune activity of dendritic cells in chronic obstructive pulmonary disease induced by air pollution particulate matter. J. Hazard Mater. 438, 129459 (2022).

Wang, Q. et al. Lymph node-targeting nanovaccines for cancer immunotherapy. J. Control Rel. 351, 102–122 (2022).

Wedekind, M. F., Wagner, L. M. & Cripe, T. P. Immunotherapy for osteosarcoma: Where do we go from here? Pediatr. Blood Cancer 65, e27227 (2018).

Dallal, R. M. et al. Paucity of dendritic cells in pancreatic cancer. Surgery 131, 135–138 (2002).

Morales, E., Olson, M., Iglesias, F., Luetkens, T. & Atanackovic, D. Targeting the tumor microenvironment of Ewing sarcoma. Immunotherapy 13, 1439–1451 (2021).

Reinhardt, B. et al. Long-term outcomes after gene therapy for adenosine deaminase severe combined immune deficiency. Blood 138, 1304–1316 (2021).

Mackall, C. L. et al. A pilot study of consolidative immunotherapy in patients with high-risk pediatric sarcomas. Clin. Cancer Res. 14, 4850–4858 (2008).

Ma, L. et al. Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor. Science 365, 162–168 (2019).

Krishnadas, D. K. et al. A phase I trial combining decitabine/dendritic cell vaccine targeting MAGE-A1, MAGE-A3 and NY-ESO-1 for children with relapsed or therapy-refractory neuroblastoma and sarcoma. Cancer Immunol. Immunother. 64, 1251–1260 (2015).

Letizia, M. et al. Store-operated calcium entry controls innate and adaptive immune cell function in inflammatory bowel disease. EMBO Mol. Med. 14, e15687 (2022).

Xiao, H. et al. Effect of the cytokine levels in serum on osteosarcoma. Tumour Biol. 35, 1023–1028 (2014).

Challagundla, N., Shah, D., Yadav, S. & Agrawal-Rajput, R. Saga of monokines in shaping tumour-immune microenvironment: Origin to execution. Cytokine 157, 155948 (2022).

Wang, J., Mi, S., Ding, M., Li, X. & Yuan, S. Metabolism and polarization regulation of macrophages in the tumor microenvironment. Cancer Lett. 543, 215766 (2022).

Burgess, M. & Tawbi, H. Immunotherapeutic approaches to sarcoma. Curr. Treat. Options Oncol. 16, 26 (2015).

Propper, D. J. & Balkwill, F. R. Harnessing cytokines and chemokines for cancer therapy. Nat. Rev. Clin. Oncol. 19, 237–253 (2022).

Tuzlak, S. et al. Repositioning T(H) cell polarization from single cytokines to complex help. Nat. Immunol. 22, 1210–1217 (2021).

Wang, T. & Secombes, C. J. The cytokine networks of adaptive immunity in fish. Fish. Shellfish Immunol. 35, 1703–1718 (2013).

Kubo, S. et al. Early B cell factor 4 modulates FAS-mediated apoptosis and promotes cytotoxic function in human immune cells. Proc. Natl Acad. Sci. USA 119, e2208522119 (2022).

Zebley, C. C. et al. Proinflammatory cytokines promote TET2-mediated DNA demethylation during CD8 T cell effector differentiation. Cell Rep. 37, 109796 (2021).

Kitazawa, T. & Streilein, J. W. Studies on delayed systemic effects of ultraviolet B radiation on the induction of contact hypersensitivity, 3. Dendritic cells from secondary lymphoid organs are deficient in interleukin-12 production and capacity to promote activation and differentiation of T helper type 1 cells. Immunology 99, 296–304 (2000).

Rudman, S. M. et al. A phase 1 study of AS1409, a novel antibody-cytokine fusion protein, in patients with malignant melanoma or renal cell carcinoma. Clin. Cancer Res. 17, 1998–2005 (2011).

Srinoulprasert, Y. et al. Differential cytokine profiles produced by anti-epileptic drug re-exposure of peripheral blood mononuclear cells derived from severe anti-epileptic drug patients and non-allergic controls. Cytokine 157, 155951 (2022).

Buddingh, E. P. et al. Chemotherapy-resistant osteosarcoma is highly susceptible to IL-15-activated allogeneic and autologous NK cells. Cancer Immunol. Immunother. 60, 575–586 (2011).

Meazza, C. et al. Primary metastatic osteosarcoma: results of a prospective study in children given chemotherapy and interleukin-2. Med. Oncol. 34, 191 (2017).

Rivoltini, L. et al. Phenotypic and functional analysis of lymphocytes infiltrating paediatric tumours, with a characterization of the tumour phenotype. Cancer Immunol. Immunother. 34, 241–251 (1992).

Nasr, S. et al. A phase I study of interleukin-2 in children with cancer and evaluation of clinical and immunologic status during therapy. A Pediatric Oncology Group Study. Cancer 64, 783–788 (1989).

Rodig, S. J. et al. MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. Sci. Transl. Med. 10, eaar3342 (2018).

Marin-Acevedo, J. A. et al. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J. Hematol. Oncol. 11, 39 (2018).

Melaiu, O., Lucarini, V., Giovannoni, R., Fruci, D. & Gemignani, F. News on immune checkpoint inhibitors as immunotherapy strategies in adult and pediatric solid tumors. Semin Cancer Biol. 79, 18–43 (2022).

Kubo, T. et al. Immunopathological basis of immune-related adverse events induced by immune checkpoint blockade therapy. Immunol. Med. 45, 108–118 (2022).

Kyu Shim, M., Yang, S., Sun, I. C. & Kim, K. Tumor-activated carrier-free prodrug nanoparticles for targeted cancer Immunotherapy: Preclinical evidence for safe and effective drug delivery. Adv. Drug Deliv. Rev. 183, 114177 (2022).

Dhupkar, P., Gordon, N., Stewart, J. & Kleinerman, E. S. Anti-PD-1 therapy redirects macrophages from an M2 to an M1 phenotype inducing regression of OS lung metastases. Cancer Med. 7, 2654–2664 (2018).

Shi, M. et al. Blockage of the IDO1 pathway by charge-switchable nanoparticles amplifies immunogenic cell death for enhanced cancer immunotherapy. Acta Biomater. 150, 353–366 (2022).

Tie, Y., Tang, F., Wei, Y. Q. & Wei, X. W. Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets. J. Hematol. Oncol. 15, 61 (2022).

Liu, N., Chang, C. W., Steer, C. J., Wang, X. W. & Song, G. MicroRNA-15a/16-1 prevents hepatocellular carcinoma by disrupting the communication between Kupffer cells and regulatory T cells. Gastroenterology 162, 575–589 (2022).

Serr, I., Kral, M., Scherm, M. G. & Daniel, C. Advances in human immune system mouse models for personalized treg-based immunotherapies. Front. Immunol. 12, 643544 (2021).

Onda, M., Kobayashi, K. & Pastan, I. Depletion of regulatory T cells in tumors with an anti-CD25 immunotoxin induces CD8 T cell-mediated systemic antitumor immunity. Proc. Natl. Acad. Sci. USA 116, 4575–4582 (2019).

Hong, H. et al. Depletion of CD4+CD25+ regulatory T cells enhances natural killer T cell-mediated anti-tumour immunity in a murine mammary breast cancer model. Clin. Exp. Immunol. 159, 93–99 (2010).

Mijnheer, G. et al. Conserved human effector Treg cell transcriptomic and epigenetic signature in arthritic joint inflammation. Nat. Commun. 12, 2710 (2021).

Amoozgar, Z. et al. Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas. Nat. Commun. 12, 2582 (2021).

Liang, Y. et al. Blockade of PD-1/PD-L1 increases effector T cells and aggravates murine chronic graft-versus-host disease. Int. Immunopharmacol. 110, 109051 (2022).

Wagner, L. M. & Adams, V. R. Targeting the PD-1 pathway in pediatric solid tumors and brain tumors. Onco. Targets Ther. 10, 2097–2106 (2017).

Yoshida, K. et al. Anti-PD-1 antibody decreases tumour-infiltrating regulatory T cells. BMC Cancer 20, 25 (2020).

Thanindratarn, P., Dean, D. C., Nelson, S. D., Hornicek, F. J. & Duan, Z. Advances in immune checkpoint inhibitors for bone sarcoma therapy. J. Bone Oncol. 15, 100221 (2019).

Harrison, D. J., Geller, D. S., Gill, J. D., Lewis, V. O. & Gorlick, R. Current and future therapeutic approaches for osteosarcoma. Expert Rev. Anticancer Ther. 18, 39–50 (2018).

Cascio, M. J. et al. Canine osteosarcoma checkpoint expression correlates with metastasis and T-cell infiltrate. Vet. Immunol. Immunopathol. 232, 110169 (2021).

Shen, J. K. et al. Programmed cell death ligand 1 expression in osteosarcoma. Cancer Immunol. Res. 2, 690–698 (2014).

Mochizuki, Y. et al. Telomerase-specific oncolytic immunotherapy for promoting efficacy of PD-1 blockade in osteosarcoma. Cancer Immunol. Immunother. 70, 1405–1417 (2021).

Flem-Karlsen, K., Fodstad, Ø. & Nunes-Xavier, C. E. B7-H3 immune checkpoint protein in human cancer. Curr. Med. Chem. 27, 4062–4086 (2020).

Lee, Y. H. et al. Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function. Cell Res. 27, 1034–1045 (2017).

Wang, Y. et al. Comprehensive surfaceome profiling to identify and validate novel cell-surface targets in Osteosarcoma. Mol. Cancer Ther. 21, 903–913 (2022).

Talbot, L. J. et al. A Novel Orthotopic implantation technique for osteosarcoma produces spontaneous metastases and illustrates dose-dependent efficacy of B7-H3-CAR T Cells. Front. Immunol. 12, 691741 (2021).

Yin, S. J., Wang, W. J. & Zhang, J. Y. Expression of B7-H3 in cancer tissue during osteosarcoma progression in nude mice. Genet. Mol. Res. 14, 14253–14261 (2015).

Wang, L. et al. Roles of coinhibitory molecules B7-H3 and B7-H4 in esophageal squamous cell carcinoma. Tumour Biol. 37, 2961–2971 (2016).

Majzner, R. G. et al. CAR T cells targeting B7-H3, a pan-cancer antigen, demonstrate potent preclinical activity against pediatric solid tumors and brain tumors. Clin. Cancer Res. 25, 2560–2574 (2019).

Wang, L. et al. The tumor suppressor miR-124 inhibits cell proliferation and invasion by targeting B7-H3 in osteosarcoma. Tumour Biol. 37, 14939–14947 (2016).

Gill, J. & Gorlick, R. Advancing therapy for osteosarcoma. Nat. Rev. Clin. Oncol. 18, 609–624 (2021).

Whittle, S. B. et al. Charting a path for prioritization of novel agents for clinical trials in osteosarcoma: A report from the Children’s Oncology Group New Agents for Osteosarcoma Task Force. Pediatr. Blood Cancer 68, e29188 (2021).

Wang, L., Zhang, G. C., Kang, F. B., Zhang, L. & Zhang, Y. Z. hsa_circ0021347 as a potential target regulated by B7-H3 in Modulating the malignant characteristics of Osteosarcoma. Biomed. Res. Int. 2019, 9301989 (2019).

Aggarwal, C. et al. Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial. J. Immunother. Cancer 10, e004424 (2022).

Hińcza-Nowak, K. et al. Immune profiling of medullary thyroid cancer-an opportunity for immunotherapy. Genes 12, 1534 (2021).

Callahan, M. K., Postow, M. A. & Wolchok, J. D. CTLA-4 and PD-1 pathway blockade: combinations in the clinic. Front. Oncol. 4, 385 (2014).

Krummel, M. F. & Allison, J. P. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J. Exp. Med. 182, 459–465 (1995).

Xiang, J., Gu, X., Qian, S. & Chen, Z. Graded function of CD80 and CD86 in initiation of T-cell immune response and cardiac allograft survival. Transpl. Int. 21, 163–168 (2008).

Kennedy, A. et al. Differences in CD80 and CD86 transendocytosis reveal CD86 as a key target for CTLA-4 immune regulation. Nat. Immunol. 23, 1365–1378 (2022).

Heeren, A. M. et al. Immune landscape in vulvar cancer-draining lymph nodes indicates distinct immune escape mechanisms in support of metastatic spread and growth. J. Immunother. Cancer 9, e003623 (2021).

Pinato, D. J. et al. Trans-arterial chemoembolization as a loco-regional inducer of immunogenic cell death in hepatocellular carcinoma: implications for immunotherapy. J. Immunother. Cancer 9, e003311 (2021).

Wolchok, J. D. et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 11, 155–164 (2010).

Markel, J. E. et al. Using the spleen as an in vivo systemic immune barometer alongside osteosarcoma disease progression and immunotherapy with α-PD-L1. Sarcoma 2018, 8694397 (2018).

Wang, S. D. et al. The role of CTLA-4 and PD-1 in anti-tumor immune response and their potential efficacy against osteosarcoma. Int. Immunopharmacol. 38, 81–89 (2016).

Liu, S., Geng, P., Cai, X. & Wang, J. Comprehensive evaluation of the cytotoxic T-lymphocyte antigen-4 gene polymorphisms in risk of bone sarcoma. Genet. Test. Mol. Biomark. 18, 574–579 (2014).

He, J. et al. Association between CTLA-4 genetic polymorphisms and susceptibility to osteosarcoma in Chinese Han population. Endocrine 45, 325–330 (2014).

Hingorani, P. et al. Increased CTLA-4(+) T cells and an increased ratio of monocytes with loss of class II (CD14(+)HLA-DR(lo/neg)) found in aggressive pediatric sarcoma patients. J. Immunother. Cancer 3, 35 (2015).

Deppong, C. M. et al. CTLA4Ig inhibits effector T cells through regulatory T cells and TGF-β. J. Immunol. 191, 3082–3089 (2013).

Merchant, M. S. et al. Phase I Clinical trial of Ipilimumab in pediatric patients with advanced solid tumors. Clin. Cancer Res. 22, 1364–1370 (2016).

Carnevale, J. et al. RASA2 ablation in T cells boosts antigen sensitivity and long-term function. Nature 609, 174–182 (2022).

Nguyen, A. et al. HDACi promotes inflammatory remodeling of the tumor microenvironment to enhance epitope spreading and antitumor immunity. J. Clin. Invest. 132, e159283 (2022).

Huang, R. et al. GP96 and SMP30 protein priming of dendritic cell vaccination induces a more potent CTL Response against Hepatoma. J. Health. Eng. 2022, 2518847 (2022).

Bolhassani, A. et al. Modified DCs and MSCs with HPV E7 antigen and small HSPS: Which one is the most potent strategy for eradication of tumors? Mol. Immunol. 108, 102–110 (2019).

Qi, T., McGrath, K., Ranganathan, R., Dotti, G. & Cao, Y. Cellular kinetics: A clinical and computational review of CAR-T cell pharmacology. Adv. Drug Deliv. Rev. 188, 114421 (2022).

Elnaggar, M. et al. Triple MAPK inhibition salvaged a relapsed post-BCMA CAR-T cell therapy multiple myeloma patient with a BRAF V600E subclonal mutation. J. Hematol. Oncol. 15, 109 (2022).

Yee, C. & Lizee, G. A. Personalized therapy: tumor antigen discovery for adoptive cellular therapy. Cancer J. 23, 144–148 (2017).

Wang, W. et al. Hepatobiliary Tumor Organoids reveal HLA class I neoantigen landscape and antitumoral activity of neoantigen peptide enhanced with immune checkpoint inhibitors. Adv. Sci. 9, e2105810 (2022).

Salawu, A. et al. A Phase 2 trial of Afatinib in patients with solid tumors that harbor genomic aberrations in the HER family: The MOBILITY3 Basket Study. Target Oncol. 17, 271–281 (2022).

Ahmed, N. et al. Human Epidermal Growth Factor Receptor 2 (HER2) -Specific Chimeric antigen receptor-modified T cells for the immunotherapy of HER2-Positive Sarcoma. J. Clin. Oncol. 33, 1688–1696 (2015).

Geary, R. L., Corrigan, L. R., Carney, D. N. & Higgins, M. J. Osteosarcoma and second malignant neoplasms: a case series. Ir. J. Med. Sci. 188, 1163–1167 (2019).

Huang, G. et al. Genetically modified T cells targeting interleukin-11 receptor α-chain kill human osteosarcoma cells and induce the regression of established osteosarcoma lung metastases. Cancer Res. 72, 271–281 (2012).

Yang, Q. et al. Membrane-anchored and tumor-targeted IL12 (attIL12)-PBMC therapy for osteosarcoma. Clin. Cancer Res. 28, 3862–3873 (2022).

Brentjens, R. J. et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5, 177ra138 (2013).

Lee, D. W. et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385, 517–528 (2015).

Davila, M. L. et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6, 224ra225 (2014).

Théoleyre, S. et al. Phenotypic and functional analysis of lymphocytes infiltrating osteolytic tumors: use as a possible therapeutic approach of osteosarcoma. BMC Cancer 5, 123 (2005).

Wang, Y. et al. Anti-CD166/4-1BB chimeric antigen receptor T cell therapy for the treatment of osteosarcoma. J. Exp. Clin. Cancer Res. 38, 168 (2019).

Zhao, Q. et al. Engineered TCR-T cell immunotherapy in anticancer precision medicine: pros and cons. Front. Immunol. 12, 658753 (2021).

Brameshuber, M. et al. Monomeric TCRs drive T cell antigen recognition. Nat. Immunol. 19, 487–496 (2018).

Muthana, M. et al. Macrophage delivery of an oncolytic virus abolishes tumor regrowth and metastasis after chemotherapy or irradiation. Cancer Res 73, 490–495 (2013).

Hinrichs, C. S. & Rosenberg, S. A. Exploiting the curative potential of adoptive T-cell therapy for cancer. Immunol. Rev. 257, 56–71 (2014).

Sarnaik, A. A. et al. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. J. Clin. Oncol. 39, 2656–2666 (2021).

Wang, C., Li, M., Wei, R. & Wu, J. Adoptive transfer of TILs plus anti-PD1 therapy: An alternative combination therapy for treating metastatic osteosarcoma. J. Bone Oncol. 25, 100332 (2020).

Lussier, D. M., Johnson, J. L., Hingorani, P. & Blattman, J. N. Combination immunotherapy with α-CTLA-4 and α-PD-L1 antibody blockade prevents immune escape and leads to complete control of metastatic osteosarcoma. J. Immunother. Cancer 3, 21 (2015).

D’Angelo, S. P. et al. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol. 19, 416–426 (2018).

Krupka, C. et al. Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism. Leukemia 30, 484–491 (2016).

Sun, C., Dotti, G. & Savoldo, B. Utilizing cell-based therapeutics to overcome immune evasion in hematologic malignancies. Blood 127, 3350–3359 (2016).

Tabata, R., Chi, S., Yuda, J. & Minami, Y. Emerging immunotherapy for acute myeloid leukemia. Int. J. Mol. Sci. 22, 1944 (2021).

Sierro, S. R. et al. Combination of lentivector immunization and low-dose chemotherapy or PD-1/PD-L1 blocking primes self-reactive T cells and induces anti-tumor immunity. Eur. J. Immunol. 41, 2217–2228 (2011).

Fu, J. et al. Preclinical evidence that PD1 blockade cooperates with cancer vaccine TEGVAX to elicit regression of established tumors. Cancer Res. 74, 4042–4052 (2014).

Houser, K. V. et al. Safety and immunogenicity of a ferritin nanoparticle H2 influenza vaccine in healthy adults: a phase 1 trial. Nat. Med. 28, 383–391 (2022).

Wang, Z., Li, B., Ren, Y. & Ye, Z. T-cell-based immunotherapy for Osteosarcoma: challenges and opportunities. Front. Immunol. 7, 353 (2016).

Chapuis, A. G. et al. T-cell Therapy using Interleukin-21-primed Cytotoxic T-Cell Lymphocytes combined with Cytotoxic T-Cell Lymphocyte Antigen-4 blockade results in long-term cell persistence and durable tumor regression. J. Clin. Oncol. 34, 3787–3795 (2016).

Curran, M. A., Montalvo, W., Yagita, H. & Allison, J. P. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl. Acad. Sci. USA 107, 4275–4280 (2010).

Fulgenzi, C. A. M. et al. Comparative efficacy of novel combination strategies for unresectable hepatocellular carcinoma: A network metanalysis of phase III trials. Eur. J. Cancer 174, 57–67 (2022).

Ju, F. et al. Oncolytic virus expressing PD-1 inhibitors activates a collaborative intratumoral immune response to control tumor and synergizes with CTLA-4 or TIM-3 blockade. J. Immunother. Cancer 10, e004762 (2022).

Mitchell, T. C. et al. Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037). J. Clin. Oncol. 36, 3223–3230 (2018).

Long, G. V. et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 20, 1083–1097 (2019).

Yu, A. L. et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N. Engl. J. Med. 363, 1324–1334 (2010).

Kushner, B. H. et al. Humanized 3F8 anti-GD2 Monoclonal antibody dosing with granulocyte-macrophage colony-stimulating factor in patients with resistant neuroblastoma: A Phase 1 Clinical trial. JAMA Oncol. 4, 1729–1735 (2018).

Zhu, W. et al. Anti-ganglioside GD2 monoclonal antibody synergizes with cisplatin to induce endoplasmic reticulum-associated apoptosis in osteosarcoma cells. Pharmazie 73, 80–86 (2018).

Buondonno, I. et al. Endoplasmic reticulum-targeting doxorubicin: a new tool effective against doxorubicin-resistant osteosarcoma. Cell Mol. Life Sci. 76, 609–625 (2019).

Xie, L. et al. Apatinib plus camrelizumab (anti-PD1 therapy, SHR-1210) for advanced osteosarcoma (APFAO) progressing after chemotherapy: a single-arm, open-label, phase 2 trial. J. Immunother. Cancer 8, e000798 (2020).

Regan, D. P. et al. Losartan Blocks Osteosarcoma-elicited monocyte recruitment, and combined with the kinase inhibitor toceranib, exerts significant clinical benefit in canine metastatic Osteosarcoma. Clin. Cancer Res. 28, 662–676 (2022).

Mahoney, K. M., Rennert, P. D. & Freeman, G. J. Combination cancer immunotherapy and new immunomodulatory targets. Nat. Rev. Drug Discov. 14, 561–584 (2015).

Yamada, N. et al. Immunotherapy with interleukin-18 in combination with preoperative chemotherapy with ifosfamide effectively inhibits postoperative progression of pulmonary metastases in a mouse osteosarcoma model. Tumour Biol. 30, 176–184 (2009).

He, X., Lin, H., Yuan, L. & Li, B. Combination therapy with L-arginine and α-PD-L1 antibody boosts immune response against osteosarcoma in immunocompetent mice. Cancer Biol. Ther. 18, 94–100 (2017).

Kawano, M. et al. Dendritic cells combined with doxorubicin induces immunogenic cell death and exhibits antitumor effects for osteosarcoma. Oncol. Lett. 11, 2169–2175 (2016).

Zhang, Y. et al. Hyaluronate-based self-stabilized nanoparticles for immunosuppression reversion and immunochemotherapy in osteosarcoma treatment. ACS Biomater. Sci. Eng. 7, 1515–1525 (2021).

Ramos-Cardona, X. E., Luo, W. & Mohammed, S. I. Advances and challenges of CAR T therapy and suitability of animal models (Review). Mol. Clin. Oncol. 17, 134 (2022).

Wu, L. et al. Biomimetic nanocarriers guide extracellular ATP Homeostasis to remodel energy metabolism for activating innate and adaptive immunity system. Adv. Sci. 9, e2105376 (2022).

Gao, S., Yang, X., Xu, J., Qiu, N. & Zhai, G. Nanotechnology for boosting cancer immunotherapy and remodeling tumor microenvironment: the horizons in cancer treatment. ACS Nano 15, 12567–12603 (2021).

Li, Q. et al. A Three-in-One Immunotherapy Nanoweapon via Cascade-amplifying cancer-immunity cycle against tumor metastasis, relapse, and postsurgical regrowth. Nano Lett. 19, 6647–6657 (2019).

Zhang, D. et al. Cold to Hot: Rational design of a minimalist multifunctional photo-immunotherapy nanoplatform toward boosting immunotherapy capability. ACS Appl. Mater. Interfaces 11, 32633–32646 (2019).

Zhou, S. et al. Rational design of a minimalist nanoplatform to maximize immunotherapeutic efficacy: Four birds with one stone. J. Control Rel. 328, 617–630 (2020).

Ren, X. et al. An injectable hydrogel using an immunomodulating gelator for amplified tumor immunotherapy by blocking the arginase pathway. Acta Biomater. 124, 179–190 (2021).

Vitale, M. et al. Oncolytic adenoviral vector-mediated expression of an Anti-PD-L1-scFv improves anti-tumoral efficacy in a Melanoma Mouse Model. Front. Oncol. 12, 902190 (2022).

Duan, X., Chan, C. & Lin, W. Nanoparticle-mediated immunogenic cell death enables and potentiates cancer immunotherapy. Angew. Chem. Int. Ed. Engl. 58, 670–680 (2019).

Buondonno, I. et al. Mitochondria-targeted Doxorubicin: A new therapeutic strategy against Doxorubicin-Resistant Osteosarcoma. Mol. Cancer Ther. 15, 2640–2652 (2016).

Kepp, O., Senovilla, L. & Kroemer, G. Immunogenic cell death inducers as anticancer agents. Oncotarget 5, 5190–5191 (2014).

Jin, J. et al. Mitochondria-targeting polymer Micelle of Dichloroacetate induced pyroptosis to enhance osteosarcoma immunotherapy. ACS Nano, 16, 10327–10340 (2022).

Ge, Y. X. et al. Enhancement of anti-PD-1/PD-L1 immunotherapy for osteosarcoma using an intelligent autophagy-controlling metal organic framework. Biomaterials 282, 121407 (2022).

Liao, J., Han, R., Wu, Y. & Qian, Z. Review of a new bone tumor therapy strategy based on bifunctional biomaterials. Bone Res. 9, 18 (2021).

Yu, W. et al. A review and outlook in the treatment of osteosarcoma and other deep tumors with photodynamic therapy: from basic to deep. Oncotarget 8, 39833–39848 (2017).

Huang, X. et al. Rationally designed Heptamethine Cyanine photosensitizers that amplify tumor-specific endoplasmic reticulum stress and boost antitumor immunity. Small 18, e2202728 (2022).

Wang, C. et al. Immunological responses triggered by photothermal therapy with carbon nanotubes in combination with anti-CTLA-4 therapy to inhibit cancer metastasis. Adv. Mater. 26, 8154–8162 (2014).

Lou, H. et al. A small-molecule based organic nanoparticle for photothermal therapy and near-infrared-iib imaging. ACS Appl. Mater. Interfaces 14, 35454–35465 (2022).

Huang, X. et al. Black phosphorus-synergic nitric oxide nanogasholder spatiotemporally regulates tumor microenvironments for self-amplifying immunotherapy. ACS Appl Mater. Interfaces 14, 37466–37477 (2022).

Guevara, M. L., Persano, F. & Persano, S. Nano-immunotherapy: Overcoming tumour immune evasion. Semin Cancer Biol. 69, 238–248 (2021).

Tian, H. et al. A targeted nanomodulator capable of manipulating tumor microenvironment against metastasis. J. Control. Release 348, 590-600 (2022).

Zhu, M. et al. Bioinspired design of seco-chlorin photosensitizers to overcome phototoxic effects in photodynamic therapy. Angew. Chem. Int. Ed. Engl. 61, e202204330 (2022).

Ren, Q., Yi, C., Pan, J., Sun, X. & Huang, X. Smart Fe(3)O(4)@ZnO core-shell nanophotosensitizers potential for combined chemo and photodynamic skin cancer therapy controlled by UVA radiation. Int. J. Nanomed. 17, 3385–3400 (2022).

Li, Z. et al. Immunogenic cell death activates the tumor immune microenvironment to boost the immunotherapy efficiency. Adv. Sci. 9, e2201734 (2022).

Alves, C. G. et al. Heptamethine cyanine-loaded nanomaterials for cancer immuno-photothermal/photodynamic therapy: a review. Pharmaceutics 14, 1015 (2022).

Chen, Q., Chen, M. & Liu, Z. Local biomaterials-assisted cancer immunotherapy to trigger systemic antitumor responses. Chem. Soc. Rev. 48, 5506–5526 (2019).

Liu, Y. et al. In situ tumor vaccination with calcium-linked degradable coacervate nanocomplex co-delivering photosensitizer and TLR7/8 agonist to trigger effective anti-tumor immune responses. Adv. Mater. 11, e2102781 (2022).

Zhu, L., Meng, D., Wang, X. & Chen, X. Ferroptosis-driven nanotherapeutics to reverse drug resistance in tumor microenvironment. ACS Appl. Bio Mater. 5, 2481–2506 (2022).

Yanase, S. et al. Enhancement of the effect of 5-aminolevulinic acid-based photodynamic therapy by simultaneous hyperthermia. Int. J. Oncol. 27, 193–201 (2005).

Ding, M. et al. A prodrug hydrogel with tumor microenvironment and near-infrared light dual-responsive action for synergistic cancer immunotherapy. Acta Biomater. 149, 334–346 (2022).

Li, Z. et al. Immunogenic cell death augmented by manganese zinc sulfide nanoparticles for metastatic Melanoma Immunotherapy. ACS Nano 16, 15471–15483 (2022).

Li, X. et al. Protein-delivering nanocomplexes with Fenton reaction-triggered cargo release to boost cancer immunotherapy. ACS Nano 16, 14982–14999 (2022).

Xiong, G. et al. Near-Infrared-II light-induced mild Hyperthermia activate Cisplatin-Artemisinin nanoparticle for enhanced chemo/chemodynamic therapy and immunotherapy. Small Methods 6, e2200379 (2022).

Fu, L., Zhang, W., Zhou, X., Fu, J. & He, C. Tumor cell membrane-camouflaged responsive nanoparticles enable MRI-guided immuno-chemodynamic therapy of orthotopic osteosarcoma. Bioact. Mater. 17, 221–233 (2022).

Jin, T., Wu, H., Wang, Y. & Peng, H. Capsaicin induces immunogenic cell death in human osteosarcoma cells. Exp. Ther. Med. 12, 765–770 (2016).

Mori, K., Rédini, F., Gouin, F., Cherrier, B. & Heymann, D. Osteosarcoma: current status of immunotherapy and future trends (Review). Oncol. Rep. 15, 693–700 (2006).

Leleux, J. & Roy, K. Micro and nanoparticle-based delivery systems for vaccine immunotherapy: an immunological and materials perspective. Adv. Health. Mater. 2, 72–94 (2013).

Musetti, S. & Huang, L. Nanoparticle-mediated remodeling of the tumor microenvironment to enhance immunotherapy. ACS Nano 12, 11740–11755 (2018).

Lybaert, L., Vermaelen, K., De Geest, B. G. & Nuhn, L. Immunoengineering through cancer vaccines - A personalized and multi-step vaccine approach towards precise cancer immunity. J. Control Rel. 289, 125–145 (2018).

Irvine, D. J., Swartz, M. A. & Szeto, G. L. Engineering synthetic vaccines using cues from natural immunity. Nat. Mater. 12, 978–990 (2013).

Maiti, G. et al. Matrix lumican endocytosed by immune cells controls receptor ligand trafficking to promote TLR4 and restrict TLR9 in sepsis. Proc. Natl Acad. Sci. USA 118, e2100999118 (2021).

Shen, C. F. et al. Innate immune responses of vaccinees determine early neutralizing antibody production after ChAdOx1nCoV-19 vaccination. Front. Immunol. 13, 807454 (2022).

Min, Y. et al. Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy. Nat. Nanotechnol. 12, 877–882 (2017).

Anderson, K. G., Stromnes, I. M. & Greenberg, P. D. Obstacles posed by the tumor microenvironment to T cell Activity: A case for synergistic therapies. Cancer Cell 31, 311–325 (2017).

Li, Q. et al. Elastic nanovaccine enhances dendritic cell-mediated tumor immunotherapy. Small 18, e2201108 (2022).

Tuohy, J. L. et al. Assessment of a novel nanoparticle hyperthermia therapy in a murine model of osteosarcoma. Vet. Surg. 47, 1021–1030 (2018).

Richard-Fiardo, P. et al. Effect of fractalkine-Fc delivery in experimental lung metastasis using DNA/704 nanospheres. Cancer Gene Ther. 18, 761–772 (2011).

Wang, G. et al. The Anti-fibrosis drug Pirfenidone modifies the immunosuppressive tumor microenvironment and prevents the progression of renal cell carcinoma by inhibiting tumor autocrine TGF-β. Cancer Biol. Ther. 23, 150–162 (2022).

Zhang, J. et al. Arginine supplementation targeting tumor-killing immune cells reconstructs the tumor microenvironment and enhances the antitumor immune response. ACS Nano, 16, 12964–12978 (2022).

Galon, J. & Bruni, D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat. Rev. Drug Disco. 18, 197–218 (2019).

Wang, M. et al. Pyroptosis remodeling tumor microenvironment to enhance pancreatic cancer immunotherapy driven by membrane anchoring photosensitizer. Adv. Sci. 9, e2202914 (2022).

Wu, P. et al. Manipulating offense and defense signaling to fight cold tumors with carrier-free nanoassembly of fluorinated Prodrug and siRNA. Adv. Mater. 34, e2203019 (2022).

Björnmalm, M., Thurecht, K. J., Michael, M., Scott, A. M. & Caruso, F. Bridging bio-nano science and cancer nanomedicine. ACS Nano 11, 9594–9613 (2017).

Li, T. et al. Spatially targeting and regulating tumor-associated macrophages using a raspberry-like micellar system sensitizes pancreatic cancer chemoimmunotherapy. Nanoscale 14, 13098–13112 (2022).

Xia, T. et al. Immune cell atlas of cholangiocarcinomas reveals distinct tumor microenvironments and associated prognoses. J. Hematol. Oncol. 15, 37 (2022).

Dai, Y., Xu, C., Sun, X. & Chen, X. Nanoparticle design strategies for enhanced anticancer therapy by exploiting the tumour microenvironment. Chem. Soc. Rev. 46, 3830–3852 (2017).

Bhatia, S. N., Chen, X., Dobrovolskaia, M. A. & Lammers, T. Cancer nanomedicine. Nat. Rev. Cancer 22, 550–556 (2022).

Sanseviero, E., Kim, R. & Gabrilovich, D. I. Isolation and phenotyping of splenic myeloid-derived suppressor cells in murine cancer Models. Methods Mol. Biol. 2236, 19–28 (2021).

Chen, H. et al. METTL3 inhibits antitumor immunity by targeting m(6)A-BHLHE41-CXCL1/CXCR2 axis to promote colorectal cancer. Gastroenterology 163, 891–907 (2022).

Fan, Q. et al. Nanoengineering a metal-organic framework for osteosarcoma chemo-immunotherapy by modulating indoleamine-2,3-dioxygenase and myeloid-derived suppressor cells. J. Exp. Clin. Cancer Res. 41, 162 (2022).

Barth, B. M. et al. PhotoImmunoNanoTherapy reveals an anticancer role for sphingosine kinase 2 and dihydrosphingosine-1-phosphate. ACS Nano 7, 2132–2144 (2013).

Guo, R. et al. NIR responsive injectable nanocomposite thermogel system against osteosarcoma recurrence. Macromol. Rapid Commun. 43, e2200255 (2022).

Yu, W. et al. Autophagy inhibitor enhance ZnPc/BSA nanoparticle induced photodynamic therapy by suppressing PD-L1 expression in osteosarcoma immunotherapy. Biomaterials 192, 128–139 (2019).

Raglow, Z. et al. Targeting glycans for CAR therapy: The advent of sweet CARs. Mol. Ther. 30, 2881–2890 (2022).

Klatt, M. G. et al. A TCR mimic CAR T cell specific for NDC80 is broadly reactive with solid tumors and hematologic malignancies. Blood 140, 861–874 (2022).

Pant, A. & Jackson, C. M. Supercharged chimeric antigen receptor T cells in solid tumors. J. Clin. Invest. 132, e162322 (2022).

Li, H. et al. Scattered seeding of CAR T cells in solid tumors augments anticancer efficacy. Natl. Sci. Rev. 9, nwab172 (2022).

Luo, M., Zhang, H., Zhu, L., Xu, Q. & Gao, Q. CAR-T cell therapy: challenges and optimization. Crit. Rev. Immunol. 41, 77–87 (2021).

Zuo, Y. H., Zhao, X. P. & Fan, X. X. Nanotechnology-based chimeric antigen receptor T-cell therapy in treating solid tumor. Pharmacol. Res. 184, 106454 (2022).

Wang, G. et al. CXCL11-armed oncolytic adenoviruses enhance CAR-T cell therapeutic efficacy and reprogram tumor microenvironment in glioblastoma. Mol. Ther. 31, 134–153 (2023).

Young, R. M., Engel, N. W., Uslu, U., Wellhausen, N. & June, C. H. Next-generation CAR T-cell therapies. Cancer Discov. 12, 1625–1633 (2022).

Ma, X. et al. Interleukin-23 engineering improves CAR T cell function in solid tumors. Nat. Biotechnol. 38, 448–459 (2020).

Tian, Y., Li, Y., Shao, Y. & Zhang, Y. Gene modification strategies for next-generation CAR T cells against solid cancers. J. Hematol. Oncol. 13, 54 (2020).

Dangaj, D. et al. Cooperation between constitutive and inducible chemokines enables T cell engraftment and immune attack in solid tumors. Cancer Cell 35, 885–900.e810 (2019).

Chen, X. et al. Enhancing adoptive T cell therapy for solid tumor with cell-surface anchored immune checkpoint inhibitor nanogels. Nanomedicine 45, 102591 (2022).

Kiru, L. et al. In vivo imaging of nanoparticle-labeled CAR T cells. Proc. Natl. Acad. Sci. USA 119, e2102363119 (2022).

Song, Y. J. et al. Immune landscape of the tumor microenvironment identifies prognostic gene signature CD4/CD68/CSF1R in Osteosarcoma. Front. Oncol. 10, 1198 (2020).

Bishop, M. W., Janeway, K. A. & Gorlick, R. Future directions in the treatment of osteosarcoma. Curr. Opin. Pediatr. 28, 26–33 (2016).

Song, Y. J. et al. Gene expression classifier reveals prognostic osteosarcoma microenvironment molecular subtypes. Front. Immunol. 12, 623762 (2021).

Yu, W., Liu, R., Zhou, Y. & Gao, H. Size-tunable strategies for a tumor targeted drug delivery system. ACS Cent. Sci. 6, 100–116 (2020).

Şimşek, M., Ataş, E., Bağrıaçık, E., Günal, A. & Ünay, B. Type 4 hypersensitivity development in a case due to mifamurtide. Turk. J. Pediatr. 62, 694–699 (2020).

van Dongen, M. et al. Anti-inflammatory M2 type macrophages characterize metastasized and tyrosine kinase inhibitor-treated gastrointestinal stromal tumors. Int J. Cancer 127, 899–909 (2010).

Wolf-Dennen, K., Gordon, N. & Kleinerman, E. S. Exosomal communication by metastatic osteosarcoma cells modulates alveolar macrophages to an M2 tumor-promoting phenotype and inhibits tumoricidal functions. Oncoimmunology 9, 1747677 (2020).

Locati, M., Curtale, G. & Mantovani, A. Diversity, mechanisms, and significance of macrophage plasticity. Annu. Rev. Pathol. 15, 123–147 (2020).

Tsagozis, P., Eriksson, F. & Pisa, P. Zoledronic acid modulates antitumoral responses of prostate cancer-tumor associated macrophages. Cancer Immunol. Immunother. 57, 1451–1459 (2008).

Punzo, F. et al. Mifamurtide and TAM-like macrophages: effect on proliferation, migration and differentiation of osteosarcoma cells. Oncotarget 11, 687–698 (2020).

Ségaliny, A. I. et al. Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment. Int. J. Cancer 137, 73–85 (2015).

Guan, Y. et al. Inhibition of IL-18-mediated myeloid derived suppressor cell accumulation enhances anti-PD1 efficacy against osteosarcoma cancer. J. Bone Oncol. 9, 59–64 (2017).

Hu, J. et al. Cell membrane-anchored and tumor-targeted IL-12 (attIL12)-T cell therapy for eliminating large and heterogeneous solid tumors. J. Immunother. Cancer 10, e003633 (2022).

Jeong, S. N. & Yoo, S. Y. Novel oncolytic virus armed with cancer suicide gene and normal vasculogenic gene for improved anti-tumor activity. Cancers 12, 1070 (2020).

Yahiro, K. et al. Activation of TLR4 signaling inhibits progression of osteosarcoma by stimulating CD8-positive cytotoxic lymphocytes. Cancer Immunol. Immunother. 69, 745–758 (2020).

Xin Yu, J. et al. Trends in clinical development for PD-1/PD-L1 inhibitors. Nat. Rev. Drug Discov. 19, 163–164 (2020).

Gao, W., Zhou, J. & Ji, B. Evidence of Interleukin 21 reduction in Osteosarcoma patients due to PD-1/PD-L1-mediated suppression of follicular helper T cell functionality. DNA Cell Biol. 36, 794–800 (2017).

Alsaab, H. O. et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front. Pharm. 8, 561 (2017).

Li, Y. & Yee, C. IL-21 mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes. Blood 111, 229–235 (2008).

Kraehenbuehl, L., Weng, C. H., Eghbali, S., Wolchok, J. D. & Merghoub, T. Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways. Nat. Rev. Clin. Oncol. 19, 37–50 (2022).

Huang, W., Ran, R., Shao, B. & Li, H. Prognostic and clinicopathological value of PD-L1 expression in primary breast cancer: a meta-analysis. Breast Cancer Res. Treat. 178, 17–33 (2019).

Chi, Y. et al. Redox-sensitive and hyaluronic acid functionalized liposomes for cytoplasmic drug delivery to osteosarcoma in animal models. J. Control Rel. 261, 113–125 (2017).

Yin, J. et al. MXene-based hydrogels endow polyetheretherketone with effective osteogenicity and combined treatment of osteosarcoma and bacterial infection. ACS Appl Mater. Interfaces 12, 45891–45903 (2020).

Yang, F., Wen, X., Ke, Q. F., Xie, X. T. & Guo, Y. P. pH-responsive mesoporous ZSM-5 zeolites/chitosan core-shell nanodisks loaded with doxorubicin against osteosarcoma. Mater. Sci. Eng. C. Mater. Biol. Appl. 85, 142–153 (2018).

Huang, X. et al. Delivery of MutT homolog 1 inhibitor by functionalized graphene oxide nanoparticles for enhanced chemo-photodynamic therapy triggers cell death in osteosarcoma. Acta Biomater. 109, 229–243 (2020).

Zhang, Y. et al. 3D-printed bioceramic scaffolds with a Fe(3)O(4)/graphene oxide nanocomposite interface for hyperthermia therapy of bone tumor cells. J. Mater. Chem. B 4, 2874–2886 (2016).

Yue, J. et al. Bull serum albumin coated Au@Agnanorods as SERS probes for ultrasensitive osteosarcoma cell detection. Talanta 150, 503–509 (2016).

Miao, Y. et al. Single-walled carbon nanotube: One specific inhibitor of cancer stem cells in osteosarcoma upon downregulation of the TGFβ1 signaling. Biomaterials 149, 29–40 (2017).

Li, Y., Hou, H., Zhang, P. & Zhang, Z. Co-delivery of doxorubicin and paclitaxel by reduction/pH dual responsive nanocarriers for osteosarcoma therapy. Drug Deliv. 27, 1044–1053 (2020).

Gonçalves, M. et al. Dendrimer-assisted formation of fluorescent nanogels for drug delivery and intracellular imaging. Biomacromolecules 15, 492–499 (2014).

Wang, S. Q., Zhang, Q., Sun, C. & Liu, G. Y. Ifosfamide-loaded lipid-core-nanocapsules to increase the anticancer efficacy in MG63 osteosarcoma cells. Saudi J. Biol. Sci. 25, 1140–1145 (2018).

Wei, H. et al. A nanodrug consisting of doxorubicin and exosome derived from mesenchymal stem cells for osteosarcoma treatment in vitro. Int. J. Nanomed. 14, 8603–8610 (2019).