STAT3 regulates CD8+ T cell differentiation and functions in cancer and acute infection

In cancer, persistent antigens drive CD8(+) T cell differentiation into exhausted progenitor (T-ex(prog)) and terminally exhausted (T-ex(term)) cells. However, how the extrinsic and intrinsic regulatory mechanisms cooperate during this process still remains not well understood. Here, we found that STAT3 signaling plays essential roles in promoting intratumor T-ex(term) cell development by enhancing their effector functions and survival, which results in better tumor control. In tumor microenvironments, STAT3 is predominantly activated by IL-10 and IL-21, but not IL-6. Besides, STAT3 also plays critical roles in the development and function of terminally differentiated effector CD8(+) T cells in acute infection. Mechanistically, STAT3 transcriptionally promotes the expression of effector function-related genes, while it suppresses those expressed by the progenitor T-ex subset. Moreover, STAT3 functions in collaboration with BATF and IRF4 to mediate chromatin activation at the effector gene loci. Thus, we have elucidated the roles of STAT3 signaling in terminally differentiated CD8(+) T cell development, especially in cancer, which benefits the development of more effective immunotherapies against tumors. Sun et al. found that STAT3, activated by IL-10 and IL-21, regulates the terminal differentiation of effector CD8(+) T cells in cancer and also plays an important role in effector CD8(+) T cells in acute infection.