Transcription factor c-Maf drives Th17-dependent activation of CD8⁺ T cells to sustain anti-tumor immunity

Within the tumor microenvironment (TME), Th17 cells exhibit a dual role in tumor progression. Although IL-17A, IL-17F, and IL-21 have been reported to exert anti-tumor effects, the intrinsic mechanisms underlying Th17-mediated tumor suppression remain poorly understood.The transcription factor c-Maf is a known regulator of cytokine production in CD4⁺ T-cell subsets. To investigate its role in tumor immunity, we generated mice with c-Maf-deficient CD4 + T cells (). In both subcutaneous tumor models and an orthotopic colorectal cancer model induced by AOM/DSS treatment, mice developed significantly larger tumors than littermate controls, demonstrating that c-Maf expression in CD4⁺ T cell is critical for anti-tumor immunity. Analysis of tumor-infiltrating lymphocytes (TILs) from MC38 tumor-bearing mice showed a marked reduction in Tbet⁺ and IFN-gamma⁺ Th1 cells, as well as RORgammat⁺, IL-17A⁺, and IL-21⁺ Th17 cells. Although CD8⁺ T cells expressed comparable levels of c-Maf in both genotypes, mice displayed significantly reduced CD8⁺ T-cell cytotoxicity, including lower expression of CD107a, granzyme B, and IFN-gamma. These findings indicate that c-Maf deficiency diminishes anti-tumor Th1 and Th17 responses and impairs CD8⁺ T-cell function within the TME. To directly assess the role of c-Maf in Th1 and Th17 cells, we performed adoptive transfers of OT-II⁺ Th1 or Th17 cells. Transfer of c-Maf-deficient Th17 cells resulted in significantly impaired tumor control compared to WT Th17 cells, whereas Th1 cell transfer showed no genotype-dependent differences. This indicates that c-Maf selectively enhances the anti-tumor activity of Th17 cells. Furthermore, transfer of WT OT-II⁺ Th17 cells increased CD8⁺ T-cell cytotoxicity in recipient mice, suggesting that c-Maf ⁺ Th17 cells promote CD8⁺ T-cell activation. Consistent with this, neither WT nor c-Maf-deficient Th17 cells controll tumor growth when transferred into Rag1⁻/⁻ mice lacking T and B cells, demonstrating that the anti-tumor activity of Th17 cells requires CD8⁺ T cells. Mechanistically, co-culture experiments revealed that the CD8⁺ T-cell cytotoxic enhancement mediated by WT Th17 cells was abolished upon blockade of either IL-17A or IL-21. These results indicate that c-Maf promotes anti-tumor immunity by regulating IL-17A and IL-21 production in Th17 cells, thereby enabling robust CD8⁺ T-cell activation. In summary, our findings identify c-Maf as a critical transcriptional regulator in Th17 cells that sustains anti-tumor immunity through a cytokine-dependent mechanism that augments CD8⁺ T-cell cytotoxic function.