甲萘醌-4 保护 CD8(+) T 细胞免受铁死亡，从而增强抗肿瘤免疫

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 K 2 , 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.