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The immunosuppressive tumor microenvironment (ITM) and low immunogenicity of tumors greatly limit cancer immunotherapy efficacy. The approach of solely depleting regulatory T cells (Tregs) cannot ameliorate ITM, but possibly worsen it since the produced apoptotic Tregs will activate the A2A signaling pathway and cause more severe immune suppression. To address it, in this work a pH-responsive polymersome (CY/ZM@CS-BPA) based on chondroitin sulfate (CS)-poly(β-amino ester) is rationally developed. In the acidic tumor microenvironment, the tertiary amine groups in the polymersome will reverse from hydrophobic to hydrophilic due to protonation, which leads to the disintegration of nanostructures and the release of cyclophosphamide (CY) and A2A receptor (A2AR) antagonist ZM241385 (ZM). CY can selectively deplete Tregs. Additionally, CY can induce immunogenic cell death (ICD) of tumor cells, which results in the proapoptotic translocation of calreticulin to the cell surface, further initiating the antitumor immune responses. ZM can inhibit the activation of the adenosine A2A pathway, subsequently preventing the differentiation of CD4+ T cells into Tregs and enhancing the cytotoxicity of CD8+ T cells. As a result, the combination of depleting regulatory T cells and blocking the A2A receptor can enhance cancer immunotherapy efficacy.
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