Menaquinone-4 protects CD8+ T cells from ferroptosis to enhance anti-tumor immunity.

Tumor-infiltrating CD8+ T cells undergo aberrant lipid accumulation in the tumor microenvironment (TME), which triggers ferroptosis, drives T cell dysfunction, and impairs anti-tumor activity. However, strategies to protect the effector functions of CD8+ T cells by preventing ferroptosis in vivo remain limited. Here, we report that menaquinone-4 (MK-4), a form of vitamin K2, serves as a potent ferroptosis inhibitor that preserves CD8+ T cell function within the TME and enhances anti-tumor activity. Specifically, we demonstrated that MK-4 acts as a potent anti-ferroptotic agent in CD8+ T cells, thereby restoring their effector cytotoxic potential. RNA sequencing (RNA-seq) analysis revealed that MK-4 reprograms the transcriptional landscape of CD8+ T cells by reversing RSL3-induced ferroptosis-related gene expression, restoring effector-associated gene expression, and mitigating dysfunction and exhaustion programs. In adoptive cell transfer models, MK-4 pretreatment effectively suppressed ferroptosis in CD8+ T cells, enhanced their effector functions, and inhibited tumor growth. Similarly, intravenous injection of MK-4 attenuated ferroptosis in endogenous CD8+ T cells and strengthened their anti-tumor capacity. Furthermore, the combination of MK-4 with anti-programmed death-1 (PD-1) antibody therapy elicits a synergistic anti-tumor effect. Collectively, our findings reveal that MK-4 preserves CD8+ T cell function by inhibiting ferroptosis, boosts anti-tumor immunity, thereby highlighting its potential as a therapeutic strategy for cancer treatment.