Immuno-Packed T-Cell-Fusogenic Liposome Empowers Adoptive T Cell Therapy for Solid Tumor Treatment.

Abstract

Adoptive T cell therapy has achieved remarkable success in certain blood cancers, but its efficacy against solid tumors remains limited by multiple immunological challenges including inadequate tumor infiltration, tumor cell's immune tolerance, and immunosuppressive tumor microenvironment (TME). Herein, a one-step cell engineering strategy is reported to enhance T cell therapy for solid tumors using an immuno-packed T-cell-fusogenic liposome (IMPACTFUL). Through membrane fusion, IMPACTFUL simultaneously decorates therapeutic T cells with ^DPPA peptides on their surface and delivers interleukin-12 mRNA-loaded magnetic nanoparticle cores (MNP/IL-12) into the cytoplasm. MNP/IL-12 internalization grants T cells with effective tumor targeting under external magnet and TME reversion through IL-12 expression. ^DPPA peptide presentation enables T cells to overcome tumor cells' immune tolerance through PD-L1 checkpoint blockade. In a murine solid tumor model, IMPACTFUL-engineered T cells infiltrate tumors more effectively, resist exhaustion, and induce a more pro-inflammatory TME, leading to significantly suppressed tumor growth compared to unmodified T cells. Together, IMPACTFUL can empower adoptive T cell therapy by endowing T cells with multiple complementary functions in a single step. This approach offers a versatile platform to improve the therapeutic outcomes of T cell therapies against solid tumors and can accelerate their translation to clinical settings.