Glycolysis-inhibiting tumor cell-derived microparticles to enhance immunogenic cell death for synergistic cancer immunotherapy.

Abstract

In situ vaccination represents a promising cancer immunotherapy strategy, yet its efficacy in solid tumors remains limited, primarily due to the immunosuppressive tumor microenvironment (TME) and resistance to immunogenic cell death (ICD)-inducing anti-tumor treatments. Abnormal tumor metabolism, characterized by the "Warburg effect", shifts cancer cells toward glycolysis, leading to the production of immunosuppressive metabolites that hinder immune responses and comprise immunotherapy. Glycolysis inhibition has emerged as an effective strategy to overcome these challenges. In this study, we developed a combinatory therapeutic approach that co-delivers doxorubicin (DOX), a chemotherapeutic agent, and GSK2837808A (GSK), a glycolysis inhibitor, through tumor cell-derived microparticles (TMPs). The TMP platform facilitated targeted drug delivery and deep tumor penetration. The resulting formulation, TMP@DOX/GSK, effectively inhibited glycolysis, thereby enhancing tumor cell killing, promoting ICD, and amplifying immune responses. Notably, when combined with anti-CTLA-4 antibody, TMP@DOX/GSK completely eradicated melanoma in mice, prevented recurrence, and established long-term immune responses. Overall, this study demonstrates that integrating glycolysis inhibition with chemotherapy via TMP-based delivery systems can effectively overcome drug resistance, modulate the TME, and significantly improve the efficacy of anti-tumor immunotherapy.