Differentiation pathways of tumor-reactive CD8 ⁺ T cells. (A) In draining lymph nodes, a Tpex phenotype is induced in tumor-reactive CD8⁺ T cells early after priming. However, Tregs in draining lymph nodes from cold tumors can inhibit effective CD8⁺ T cell priming and induce a state of anergy comparable with what is seen in CD4⁺ T cells. CD8⁺ T cells can also adopt a unique “partial-anergy” phenotype that can be reversed by exogenous IL2 from CD4⁺ T cells. (B) In tumors, Tpex CD8⁺ T cells give rise to an intermediate-exhausted state and eventually a terminally exhausted T cells with impaired effector functions. Checkpoint blockade can expand effector-exhausted CD8⁺ T cells with significant effector function, but they still retain features of exhausted T cells. Created with BioRender. https://BioRender.com/j7c8w6c. p-MHC, peptide-MHC; EOMES, eomesodermin.