Current immune checkpoint inhibitors (ICIs) have transformed the landscape of cancer therapy. BMS-202 (BMS), a small-molecule ICI, offers advantages including lower molecular weight, easier synthesis, reduced cost, higher membrane permeability, and lower immunogenicity compared to macromolecular monoclonal antibodies. Similar to macromolecular ICIs, the efficacy of BMS is also limited by the immunosuppressive tumor microenvironment (TME). Paclitaxel (PTX), a classic anti-tumor drug, not only exerts direct cytotoxic effects but also induces immunogenic cell death (ICD), thereby remodeling the TME and potentially enhancing the efficacy of ICIs. To harness this synergistic potential, this study developed a human serum albumin (HSA)-based nanoplatform for the co-delivery of PTX and BMS, termed PTX/BMS@HSA. In vitro, PTX/BMS@HSA demonstrated significant advantages across multiple key aspects, such as enhanced cellular uptake, increased cytotoxicity, elevated ROS generation, and the induction of ICD. In vivo, this nanoparticle system demonstrated highly efficient accumulation in esophageal tumor tissues. Within the tumor microenvironment, PTX-triggered ICD and BMS-mediated blockade of PD-1/PD-L1 interaction work synergistically to reverse immunosuppression, thereby reactivating and restoring T cell function. These changes resulted in the elevation of dendritic cell maturation to 35.7 % and enhanced CD8⁺ T cell infiltration to 46.8 %. Consequently, PTX/BMS@HSA achieved remarkable tumor growth inhibition, with a suppression rate of 98.1 %, and effectively suppressed metastatic progression. This PTX/BMS@HSA presents a highly promising strategy for synergistic chemo-immunotherapy in esophageal carcinoma.
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