AbstractCD8⁺ T lymphocytes mediate potent immune responses against tumor, but the role of human CD4⁺ T cell subsets in cancer immunotherapy remains ill-defined. Herein, we exhibit that CD26 identifies three T helper subsets with distinct immunological properties in both healthy individuals and cancer patients. Although CD26^neg T cells possess a regulatory phenotype, CD26^int T cells are mainly naive and CD26^high T cells appear terminally differentiated and exhausted. Paradoxically, CD26^high T cells persist in and regress multiple solid tumors following adoptive cell transfer. Further analysis revealed that CD26^high cells have a rich chemokine receptor profile (including CCR2 and CCR5), profound cytotoxicity (Granzyme B and CD107A), resistance to apoptosis (c-KIT and Bcl2), and enhanced stemness (β-catenin and Lef1). These properties license CD26^high T cells with a natural capacity to traffic to, regress and survive in solid tumors. Collectively, these findings identify CD4⁺ T cell subsets with properties critical for improving cancer immunotherapy.