Depleting regulatory T cells (T_reg cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral T_reg cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral T_reg cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via peroxisome proliferator-activated receptor-β signaling, programming T_reg cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in T_reg cells suppressed tumor growth accompanied by a decrease in intratumoral T_reg cells and enhancement of antitumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive antitumor responses with anti-programmed cell death protein 1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrates the survival and functions of intratumoral T_reg cells, and the therapeutic potential of targeting this pathway for reprogramming the TME.

消耗调节性 T 细胞 (T _reg细胞) 以抵消肿瘤微环境 (TME) 的免疫抑制特征是一种有吸引力的癌症治疗策略；然而，由于其抑制功能的系统性损害导致的自身免疫限制了其治疗潜力。癌症免疫治疗迫切需要阐明特异性破坏肿瘤内 T _{reg细胞的方法。}我们发现 CD36 在肿瘤内 T _reg细胞中作为中枢代谢调节剂选择性上调。CD36 通过过氧化物酶体增殖物激活受体-β 信号传导微调线粒体适应性，编程 T _reg细胞以适应富含乳酸的 TME。T _reg中Cd36的基因消融细胞抑制肿瘤生长，伴随着肿瘤内 T _reg细胞的减少和肿瘤浸润淋巴细胞的抗肿瘤活性增强，而不会破坏免疫稳态。此外，针对 CD36 的抗程序性细胞死亡蛋白 1 疗法引发了附加的抗肿瘤反应。我们的研究结果揭示了协调肿瘤内 T _reg细胞的存活和功能的未探索的代谢适应，以及靶向该途径重编程 TME 的治疗潜力。