Engineered TCR-T cells secreting IFNα/anti-PD-L1 potentiate endogenous immunity to synergistically bolster the...

T cell receptor-engineered T cell (TCR-T) therapy represents a promising approach for treating solid tumors. However, its clinical efficacy remains suboptimal, primarily due to TCR-T dysfunction and insufficient endogenous immune activation within the tumor microenvironment. Here, we screen multiple cytokines and identify interferon α (IFNα) as a critical regulatory factor capable of improving the tumor microenvironment. However, systemic administration of IFNα leads to adverse effects and induces PD programmed cell death ligand 1 (PD-L1) upregulation on tumor cells. To overcome these challenges, we develop a TCR-T cell secreting IFNα/anti-PD-L1 to ensure treatment safety through dual tumor targeting via antigen-specific TCR and anti-PD-L1. Moreover, it effectively improves the tumor microenvironment and enhances TCR-T functionality by blocking PD-L1 and promoting Th1 differentiation of T cells, while simultaneously stimulating natural killer cell cytotoxicity and promoting dendritic cell maturation to mobilize endogenous immune cells. This synergistic approach enables the effective and safe eradication of solid tumors, offering a novel strategy to enhance the efficacy of TCR-T cell therapy with significant clinical translation potential.