Liver fibrosis and hepatic carcinoma (HCC) pose a huge challenge worldwide due to the lack of effective treatment options for end-stage liver diseases. According to their functions and roles, hepatic myofibroblasts mainly include nontumoral fibroblasts (mainly activated hepatic stellate cells (HSCs)), which are involved in the wound-healing process of liver fibrosis, and cancer-associated fibroblasts (CAFs) in hepatic HCC. HSCs play a significant role in regulating extracellular matrix (ECM) deposition in progressive liver fibrosis. CAFs can be derived from activated HSCs and differentiate into ECM-producing myofibroblasts. Moreover, growing evidence shows that CAFs are the primary regulators of the HCC microenvironment, releasing growth factors and cytokines and suppressing the antitumor immune response. Combined therapeutic strategies show reduced drug resistance and side effects. Nanotechnology-based combined strategies aim to improve the delivery efficiency of various therapeutic agents with reduced toxicity via multiple mechanisms. In this review, we will discuss recent developments in combinational strategies based on nanotechnology that regulate myofibroblasts and the diseased microenvironment for liver fibrosis and HCC treatment. We will also identify the major challenges that the field is facing and offer some insights for future drug discovery.

Chemotherapy remains one of the irreplaceable treatments for cancer therapy. The use of immunogenic cell death (ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells, simultaneously eliciting an antitumor immune response by promoting the recruitment of cytotoxic immune cells and production of granzyme B (GrB). However, numerous malignant cancers adaptively acquired the capacity of secreting serpinb9 (Sb9), a physiological inhibitor of GrB, which can reversibly inhibit the biological activity of GrB. To circumvent this dilemma, in this study, an integrated tailor-made nanomedicine composed of tumor-targeting peptide (Arg-Gly-Asp, RGD) decorated liposome, doxorubicin (DOX, an effective ICD inducer), and the compound 3034 (an inhibitor of Sb9), is developed (termed as D3RL) for breast cancer chemo-immunotherapy. In vitro and in vivo studies show that D3RL can directly kill tumor cells and trigger the host immune response by inducing ICD. Meanwhile, D3RL can competitively relieve the inhibition of Sb9 to GrB. The restored GrB can not only effectively induce tumor immunotherapy, but also degrade matrix components in the tumor microenvironment, consequently improving the infiltration of immune cells and the penetration of nanomedicines, which in return enhance the combined antitumor effect. Taken together, this work develops an integrated therapeutic solution for targeted production and restoration of GrB to achieve a combined chemo-immunotherapy for breast cancer.