肿瘤细胞在糖酵解和谷氨酰胺分解等合成代谢代谢增强的驱动下经历不受控制的增殖。针对这些途径抑制癌症生长是癌症治疗的策略。然而，重要的是，肿瘤反应性 T 细胞与癌细胞具有相同的代谢特征，这使得它们也容易受到这些治疗的影响。在这里，我们评估了乳酸脱氢酶 A (LDHA) 和谷氨酰胺酶 1 (GLS1)（有氧糖酵解和谷氨酰胺分解中的关键酶）的基因消融对抗肿瘤 T 细胞免疫和 T 细胞耗竭的影响。 LDHA 的缺失会严重损害 T 细胞对肿瘤和慢性感染的反应。相比之下，缺乏 GLS1 的 T 细胞可以通过参与替代途径（包括上调天冬酰胺合成酶）来补偿受损的谷氨酰胺分解，从而有效地应对肿瘤挑战和慢性感染以及免疫检查点封锁。因此，针对 GLS1 依赖性谷氨酰胺分解而非有氧糖酵解可能是癌症治疗的成功策略，特别是与免疫疗法相结合。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Tumor cells undergo uncontrolled proliferation driven by enhanced anabolic metabolism including glycolysis and glutaminolysis. Targeting these pathways to inhibit cancer growth is a strategy for cancer treatment. Critically, however, tumor-responsive T cells share metabolic features with cancer cells, making them susceptible to these treatments as well. Here, we assess the impact on anti-tumor T cell immunity and T cell exhaustion by genetic ablation of lactate dehydrogenase A (LDHA) and glutaminase1 (GLS1), key enzymes in aerobic glycolysis and glutaminolysis. Loss of LDHA severely impairs expansion of T cells in response to tumors and chronic infection. In contrast, T cells lacking GLS1 can compensate for impaired glutaminolysis by engaging alternative pathways, including upregulation of asparagine synthetase, and thus efficiently respond to tumor challenge and chronic infection as well as immune checkpoint blockade. Targeting GLS1-dependent glutaminolysis, but not aerobic glycolysis, may therefore be a successful strategy in cancer treatment, particularly in combination with immunotherapy.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.