Understanding the mechanisms underlying how T cells become dysfunctional in a tumor microenvironment (TME) will greatly benefit cancer immunotherapy. We found that increased CD36 expression in tumor-infiltrating CD8⁺ T cells, which was induced by TME cholesterol, was associated with tumor progression and poor survival in human and murine cancers. Genetic ablation of Cd36 in effector CD8⁺ T cells exhibited increased cytotoxic cytokine production and enhanced tumor eradication. CD36 mediated uptake of fatty acids by tumor-infiltrating CD8⁺ T cells in TME, induced lipid peroxidation and ferroptosis, and led to reduced cytotoxic cytokine production and impaired antitumor ability. Blocking CD36 or inhibiting ferroptosis in CD8⁺ T cells effectively restored their antitumor activity and, more importantly, possessed greater antitumor efficacy in combination with anti-PD-1 antibodies. This study reveals a new mechanism of CD36 regulating the function of CD8⁺ effector T cells and therapeutic potential of targeting CD36 or inhibiting ferroptosis to restore T cell function.

了解 T 细胞如何在肿瘤微环境 (TME) 中功能失调的机制将极大地有益于癌症免疫治疗。我们发现由 TME 胆固醇诱导的肿瘤浸润性 CD8 ^{+ T 细胞中 CD36 表达增加与人类和小鼠癌症的肿瘤进展和较差的存活率有关。}效应 CD8 ^{+ T 细胞中}Cd36的基因消融表现出增加的细胞毒性细胞因子产生和增强的肿瘤根除。^{CD36 介导 TME 中肿瘤浸润性 CD8 +} T 细胞摄取脂肪酸，诱导脂质过氧化和铁死亡，并导致细胞毒性细胞因子产生减少和抗肿瘤能力受损。阻断 CD36 或抑制 CD8 中的铁死亡⁺ T 细胞有效地恢复了它们的抗肿瘤活性，更重要的是，与抗 PD-1 抗体组合具有更大的抗肿瘤功效。本研究揭示了CD36调节CD8 ⁺效应T细胞功能的新机制以及靶向CD36或抑制铁死亡恢复T细胞功能的治疗潜力。