Enhancing TIM-3 immunotherapy with epirubicin-loaded pH sensitive fusion membrane nanoparticles for effective glioblastoma treatment.

Immune checkpoint blockade (ICB), particularly anti-programmed cell death protein 1 blockade (aPD-1), has demonstrated limited efficacy in glioblastoma (GBM) due to the tumor's highly immunosuppressive microenvironment and the restrictive blood-brain barrier (BBB). T cell immunoglobulin and mucin domain-3 (TIM-3), an emerging immune checkpoint widely expressed on various immune cells beyond just exhausted T cells, presents a promising target for GBM treatment. In this study, we engineered A2-TELM, a pH-sensitive macrophage membrane-coated nanoparticle conjugated with angiopep-2 peptide, to deliver anti-TIM-3 antibody (aTIM-3) alongside immunogenic cell death (ICD)-inducing agent Epirubicin (EPI) to brain tumors. This system achieves efficient BBB penetration and precise tumor targeting, enabling effective drug distribution and sustained presence within the tumor microenvironment. A2-TELM significantly reshapes the tumor immune microenvironment by initiating ICD, enhancing both the innate and adaptive immune response, with CD8+ T cells and macrophages essential for its anti-tumor function. This effectively inhibits GBM tumor growth, prolongs mice survival, and induces durable anti-tumor immune memory. Notably, aTIM-3 showed stronger anti-tumor effects than aPD-1 when combined with EPI in several GBM models, largely through enhanced macrophage polarization and phagocytic activity. Overall, this targeted system, which leverages chemotherapy-induced ICD to improve TIM-3 anti-tumor efficacy, holds substantial promise as a therapeutic strategy for GBM.