Limiting metabolic competition in the tumour microenvironment may increase the effectiveness of immunotherapy. Owing to its crucial role in the glucose metabolism of activated T cells, CD28 signalling has been proposed as a metabolic biosensor of T cells¹. By contrast, the engagement of CTLA-4 has been shown to downregulate T cell glycolysis¹. Here we investigate the effect of CTLA-4 blockade on the metabolic fitness of intra-tumour T cells in relation to the glycolytic capacity of tumour cells. We found that CTLA-4 blockade promotes metabolic fitness and the infiltration of immune cells, especially in glycolysis-low tumours. Accordingly, treatment with anti-CTLA-4 antibodies improved the therapeutic outcomes of mice bearing glycolysis-defective tumours. Notably, tumour-specific CD8⁺ T cell responses correlated with phenotypic and functional destabilization of tumour-infiltrating regulatory T (T_reg) cells towards IFNγ- and TNF-producing cells in glycolysis-defective tumours. By mimicking the highly and poorly glycolytic tumour microenvironments in vitro, we show that the effect of CTLA-4 blockade on the destabilization of T_reg cells is dependent on T_reg cell glycolysis and CD28 signalling. These findings indicate that decreasing tumour competition for glucose may facilitate the therapeutic activity of CTLA-4 blockade, thus supporting its combination with inhibitors of tumour glycolysis. Moreover, these results reveal a mechanism by which anti-CTLA-4 treatment interferes with T_reg cell function in the presence of glucose.

限制肿瘤微环境中的代谢竞争可能会提高免疫治疗的有效性。由于其在活化 T 细胞的葡萄糖代谢中的关键作用，CD28 信号传导已被提议作为 T 细胞¹的代谢生物传感器。相比之下，CTLA-4 的参与已被证明可下调 T 细胞糖酵解¹。在这里，我们研究了 CTLA-4 阻断对肿瘤内 T 细胞代谢适应度与肿瘤细胞糖酵解能力的影响。我们发现 CTLA-4 阻断促进了代谢适应性和免疫细胞的浸润，特别是在糖酵解低的肿瘤中。因此，用抗 CTLA-4 抗体治疗改善了患有糖酵解缺陷肿瘤的小鼠的治疗结果。值得注意的是，肿瘤特异性 CD8⁺ T 细胞反应与糖酵解缺陷型肿瘤中肿瘤浸润性调节性 T (T _reg ) 细胞对 IFNγ 和 TNF 产生细胞的表型和功能失稳相关。通过在体外模拟高糖酵解肿瘤微环境和低糖酵解肿瘤微环境，我们表明 CTLA-4 阻断对 T _reg细胞不稳定的影响取决于 T _reg细胞糖酵解和 CD28 信号传导。这些发现表明，减少肿瘤对葡萄糖的竞争可能促进 CTLA-4 阻断剂的治疗活性，从而支持其与肿瘤糖酵解抑制剂的组合。此外，这些结果揭示了抗 CTLA-4 治疗干扰 T _reg的机制葡萄糖存在下的细胞功能。