FOXOs in cancer immunity: Knowns and unknowns

In the tumor microenvironment (TME), cancer cells, stromal cells, and immune cells, along with their extracellular factors, have profound effects on either promoting or repressing anti-cancer immunity. Accumulating evidence has shown the paradoxical intrinsic role of the Forkhead box O (FOXO) family of transcription factors in cancer, which can act as a tumor repressor while also maintaining cancer stem cells. FOXOs also regulate cancer immunity. FOXOs promote antitumor activity through negatively regulating the expression of immunosuppressive proteins, such as programmed death 1 ligand 1 (PD-L1), and vascular endothelial growth factor (VEGF) in tumor cells or stromal cells, which can shape an immunotolerant state in the TME. FOXOs also intrinsically control the anti-tumor immune response as well as the homeostasis and development of immune cells, including T cells, B cells, natural killer (NK) cells, macrophages, and dendritic cells. As a cancer repressor, reviving the activity of Foxo1 forces tumor-infiltrating activated regulatory T (T_reg) cells to egress from tumor tissues. As a promoter of cancer development, Foxo3 and Foxo1 negatively regulate cytotoxicity of both CD8⁺ T cells and NK cells against tumor cells. In this review, we focus on the complex role of FOXOs in regulating cancer immunity due to the various roles that they play in cancer cells, stromal cells, and immune cells. We also speculate on some possible additional roles of FOXOs in cancer immunity based on findings regarding FOXOs in non-cancer settings, such as infectious disease.