Zbtb32 promotes CD8⁺ T cell differentiation and function in cancer

In the tumor microenvironment (TME), “exhausted” CD8⁺ T cells are classified into progenitor (T_pex) and terminally exhausted (T_tex) populations. T_pex cells, critically regulated by zinc finger and BTB domain containing 27 (Zbtb27)/Bcl6 transcription factor, could be reinvigorated during immune checkpoint blockade (ICB) therapy, while T_tex cells, characterized by stronger proliferation and cytotoxicity, play an indispensable role in tumor control. However, the mechanisms governing the differentiation into T_tex and their function remain not well understood. In this study, we identified that Zbtb32, highly expressed in CD8⁺ T_tex subset, is crucial for CD8⁺ T cells within tumors. Zbtb32, regulated by CD28 signaling, promotes the differentiation of CD8⁺ T cells into T_tex subset, enhancing their cytotoxicity, proliferation, and anti-tumor capability. Importantly, we found a competitive DNA binding between Zbtb32 and Bcl6, especially in regulation of Id2 expression. Thus, our findings demonstrate the pivotal role of Zbtb32 in CD8⁺ T cell anti-tumor function, with implications in cancer immunotherapy.