Identification of a novel human CD4+ T cell population and overcoming the immunosuppressive environment in large established tumors

T cell function is regulated by cytokines and receptor expression, notably IL-2 and CD25. While murine CD25 expression is largely restricted to Tregs, humans exhibit a CD25^low/intermediate FOXP3^– memory subset previously thought to be recently activated. We show this population is quiescent, phenotypically distinct from CD25^– memory cells, and differentially affected by IL-2 therapy in cancer patients, with no murine equivalent—highlighting translational limitations. Additionally, we demonstrate that combining OX40 agonist therapy with TGF-β receptor inhibition eradicates large tumors in mice, enhancing CD8+ T cell proliferation and function. These findings inform IL-2/CD25-targeted therapies and novel cancer immunotherapy strategies.