Vaccination rescues dysfunctional T cell therapy by amplifying rare stem-like antitumor CD8⁺ T cells

Most antitumor CD8⁺ T cells in patients exhibit dysfunctional phenotypes, limiting the efficacy of adoptive cell transfer (ACT) against cancer. Although cancer vaccines can induce antitumor stem-like T cell (T_SL) phenotypes, whether they can reverse T cell dysfunction during ACT remains unclear. Using murine neoantigen-specific tumor models, we show that concurrent neoantigen-vaccination enhances the antitumor activity of ACT-products dominated by dysfunctional T cells, relying on host antigen-presenting cells. Vaccination remodels the immunosuppressive tumor microenvironment and promotes the expansion of T_SL cells into tumors and lymphoid organs. Mechanistically, vaccination does not directly rescue dysfunctional T cells; but selectively amplifies low-frequency T_SL (as low as 0.1% in infusion) to mediate tumor control. Analysis of human dysfunctional TIL-ACT products containing scarce antitumor T_SL cells (~1%) administered to a patient with metastatic melanoma corroborated these findings, demonstrating complete clinical tumor regression, and expansion of adoptively transferred tumor-specific-TIL clonotypes only after concurrent vaccination. These data suggest that concurrent vaccines can unlock the therapeutic potential of rare stem-like T cells within otherwise ineffective dysfunctional ACT.