Lymph-node-derived stem-like but not tumor-tissue-resident CD8⁺ T cells fuel anticancer immunity

CD8⁺ T cell-mediated tumor control and efficacy of immune checkpoint blockade (ICB) are associated with both precursors of exhausted T (T_PEX) cells and tissue-resident memory T cells. Their relationships and relative contribution to tumor control, however, are insufficiently understood. Using single-cell RNA sequencing and genetic mouse models, we systematically dissected the heterogeneity and function of cytotoxic T cells in tumors and tumor-draining lymph nodes (tdLNs). We found that intratumoral TCF1⁺ T_PEX cells and their progeny acquired a tissue-residency program that limits their contribution to tumor control and ICB response. By contrast, MYB-dependent stem-like T_PEX cells residing in tdLNs sustained CD8⁺ T cell infiltration into tumors and mediated ICB response. The cytokine TGFβ was the central factor that enforced residency of intratumoral CD8⁺ T cells and limited the abundance of stem-like T_PEX cells in tdLNs, thereby restraining tumor control. A similar network of TGFβ-constrained intratumoral and extratumoral CD8⁺ T cells with precursor and residency characteristics was found in human cancer.