Regulatory T (T_reg) cells, although vital for immune homeostasis, also represent a major barrier to anti-cancer immunity, as the tumour microenvironment (TME) promotes the recruitment, differentiation and activity of these cells^1,2. Tumour cells show deregulated metabolism, leading to a metabolite-depleted, hypoxic and acidic TME³, which places infiltrating effector T cells in competition with the tumour for metabolites and impairs their function^4,5,6. At the same time, T_reg cells maintain a strong suppression of effector T cells within the TME^7,8. As previous studies suggested that T_reg cells possess a distinct metabolic profile from effector T cells^9,10,11, we hypothesized that the altered metabolic landscape of the TME and increased activity of intratumoral T_reg cells are linked. Here we show that T_reg cells display broad heterogeneity in their metabolism of glucose within normal and transformed tissues, and can engage an alternative metabolic pathway to maintain suppressive function and proliferation. Glucose uptake correlates with poorer suppressive function and long-term instability, and high-glucose conditions impair the function and stability of T_reg cells in vitro. T_reg cells instead upregulate pathways involved in the metabolism of the glycolytic by-product lactic acid. T_reg cells withstand high-lactate conditions, and treatment with lactate prevents the destabilizing effects of high-glucose conditions, generating intermediates necessary for proliferation. Deletion of MCT1—a lactate transporter—in T_reg cells reveals that lactate uptake is dispensable for the function of peripheral T_reg cells but required intratumorally, resulting in slowed tumour growth and an increased response to immunotherapy. Thus, T_reg cells are metabolically flexible: they can use ‘alternative’ metabolites in the TME to maintain their suppressive identity. Further, our results suggest that tumours avoid destruction by not only depriving effector T cells of nutrients, but also metabolically supporting regulatory populations.

调节性 T (T _reg ) 细胞虽然对免疫稳态至关重要，但也是抗癌免疫的主要障碍，因为肿瘤微环境 (TME) 会促进这些细胞的募集、分化和活性^1,2。肿瘤细胞表现出代谢失调，导致代谢物耗尽、缺氧和酸性 TME ³，这使浸润性效应 T 细胞与肿瘤竞争代谢物并损害其功能^4,5,6。同时，T _reg细胞在 TME ^7,8内保持对效应 T 细胞的强烈抑制。正如之前的研究表明，T _reg细胞具有与效应 T 细胞不同的代谢特征^9,10,11，我们假设 TME 代谢环境的改变与瘤内 T _reg细胞活性的增加有关。在这里，我们表明 T _reg细胞在正常和转化组织内的葡萄糖代谢中表现出广泛的异质性，并且可以参与替代代谢途径以维持抑制功能和增殖。葡萄糖摄取与较差的抑制功能和长期不稳定性相关，高葡萄糖条件会损害体外T _{reg细胞的功能和稳定性。}T _reg细胞反而会上调参与糖酵解副产物乳酸代谢的途径。_调节细胞细胞耐受高乳酸条件，用乳酸处理可防止高葡萄糖条件的不稳定作用，产生增殖所需的中间体。_{删除 T reg}细胞中的 MCT1（一种乳酸转运蛋白）表明，乳酸摄取对于外周 T _reg细胞的功能是可有可无的，但在肿瘤内是必需的，从而导致肿瘤生长减慢和对免疫疗法的反应增加。因此，T _reg细胞具有代谢灵活性：它们可以使用 TME 中的“替代”代谢物来维持其抑制特性。此外，我们的结果表明，肿瘤不仅通过剥夺效应 T 细胞的营养物质，而且通过代谢支持调节细胞群来避免破坏。