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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., Competing Interests: Declaration of interests A.C.A. is a member of the SAB for Tizona Therapeutics, Trishula Therapeutics, Compass Therapeutics, Zumutor Biologics, ImmuneOncia, and Excepgen, which have interests in cancer immunotherapy. A.C.A. is a paid consultant for iTeos Therapeutics and Larkspur Biosciences. A.C.A.’s interests were reviewed and managed by the Brigham and Women’s Hospital. C.M.J. is an employee of the VA Maryland Health Care System. The views reported here do not reflect the views of the VA or United States Government. C.M.J. has an equity position with Cartesian Therapeutics. L.B. is also an employee of SANA Biotechnology, Inc. Neither SANA Biotechnology nor its subsidiaries have conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)