Transcription factors remodel tumor immune microenvironment by impacting multiple immune cells

Transcription factors (TFs) are key drivers of tumorigenesis because of their crucial role in regulating aberrant gene expression. They contribute to tumor cell proliferation, invasion, and migration and play a pivotal role in enabling tumors to evade immune detection. In the tumor immune microenvironment (TIME), TFs reprogram tumor-infiltrating immune cells to exert pro-tumor and anti-tumor effects. In this review, we have proposed a novel, mechanism-driven classification of TFs, categorizing them into direct-acting, trans-cellular coordinated, and dual-role TFs. We have investigated the roles of direct-acting TFs in regulating CD8⁺ T cell exhaustion, maintaining CD8⁺ T cell effector functions, influencing regulatory T cell infiltration and epigenetic modifications, modulating the polarization and infiltration of tumor-associated macrophages, and promoting pro-tumor or anti-tumor properties of natural killer cells, dendritic cells and Myeloid-derived suppressor cells. In addition, we have emphasized the trans-cellular coordinated TFs that serve as bridges, facilitating cooperation among different immune cells to remodel the TIME. Finally, we have highlighted dual-role TFs that exhibit opposing functions dictated by distinct isoforms, splice variants, or post-translational modifications. Additionally, we highlight emerging pharmacological strategies targeting TFs, emphasizing their clinical potential to reverse TIME immunosuppression and synergize with immune checkpoint inhibitors. With an enhanced understanding of the molecular mechanisms underlying tumorimmune system interactions within the TIME, next-generation therapeutic strategies targeting TFs can be developed.