A "one-two punch" strategy to reverse immunosuppressive metabolism and activate T-cell immunity for enhanced cancer checkpoint immunotherapy.

Immune checkpoint blockade therapy, represented by CTLA-4 inhibitors like ipilimumab, faces limited clinical efficacy due to tumor immune evasion and the immunosuppressive tumor microenvironment. Particularly, metabolic reprogramming driven by hypoxia and the Warburg effect establishes an immunosuppressive microenvironment that inhibits T-cell-mediated antitumor immunity. To address this, we propose a "one-two punch" strategy designed to simultaneously enhance tumor immunogenicity and relieve T-cell suppression. This is achieved by a nanoplatform, ipilimumab&2-methoxyestradiol @PLGA (IM@PLGA), which co-delivers the CTLA-4 antibody ipilimumab and 2-methoxyestradiol (2-ME). 2-ME acts to reverse immunosuppression by inhibiting the HIF-1α/HK2 axis and induces immunogenic cell death (ICD) and autophagic cell death (ACD) for antigen exposure and dendritic cell (DC) activation. Concurrently, ipilimumab depletes regulatory T cells (Tregs), enabling robust activation of primed CD8+ T cells. In vitro and in vivo studies demonstrate that IM@PLGA effectively downregulates HIF-1α and HK2, induces ICD and ACD, promotes DC maturation, reduces intratumoral Tregs infiltration, and enhances CD8+ T cell recruitment. Furthermore, the treatment exhibits a potent abscopal effect in a metastatic tumor model. This work establishes a synergistic combination strategy that disrupts tumor metabolic defenses while boosting antitumor immunity, offering a promising approach to overcome resistance to cancer immune checkpoint blockade.