Multi-engineered T cell vaccine boosting TCR-T cell therapy enhances anti-tumor function and eradicates heterogeneous solid tumors.

T cell receptor (TCR)-engineered T cell therapy holds great promise for treating solid tumors, but the overall clinical efficacy remains limited. The vital challenge lies in the loss of TCR-targeted antigens and poor T cell persistence. Here, we demonstrate a novel approach to enhance TCR-T cell therapy and reject antigen-heterogeneous tumors through a multi-engineered T cell vaccine (Multi-Tvac). Multi-Tvac is composed of a TCR-targeted cognate peptide, tumor neoantigens, and an LAG-3Ig adjuvant signal, which significantly boosts dendritic cell (DC) maturation, enhances TCR-T cell anti-tumor function, and alleviates exhaustion phenotype. When combined with TCR-T cell therapy, Multi-Tvac induced long-lasting responses in established solid tumors resistant to TCR-T cell monotherapy. Notably, Multi-Tvac prevented antigen-loss tumor escape and achieved complete responses in an antigen-heterogeneous solid tumor model. Mechanistically, Multi-Tvac enhanced antigen presentation in secondary lymphoid organs (SLOs), orchestrating a strong endogenous immune response that primes T cells. As a proof-of-concept, our study extended T cell engineering beyond TCR-directed killing, which could perform as a therapeutic vaccination platform to empower TCR-T cells with new capabilities and overcome major barriers in the clinical treatment of solid tumors.