Tumor immunogenicity dictates reliance on TCF1 in CD8⁺ T cells for response to immunotherapy

Stem-like CD8⁺ T cells are regulated by T cell factor 1 (TCF1) and are considered requisite for immune checkpoint blockade (ICB) response. However, recent findings indicate that reliance on TCF1⁺CD8⁺ T cells for ICB efficacy may differ across tumor contexts. We find that TCF1 is essential for optimal priming of tumor antigen-specific CD8⁺ T cells and ICB response in poorly immunogenic tumors that accumulate TOX⁺ dysfunctional T cells, but is dispensable for T cell priming and therapy response in highly immunogenic tumors that efficiently expand transitory effectors. Importantly, improving T cell priming by vaccination or by enhancing antigen presentation on tumors rescues the defective responses of TCF1-deficient CD8⁺ T cells upon ICB in poorly immunogenic tumors. Our study highlights TCF1's role during the early stages of anti-tumor CD8⁺ T cell responses with important implications for guiding optimal therapeutic interventions in cancers with low TCF1⁺CD8⁺ T cells and low-neo-antigen expression.