Despite its outstanding clinical success, immune checkpoint blockade remains ineffective in many patients. Accordingly, combination therapy capable of achieving greater antitumor immunity is urgently required. Here, we report that limiting glutamine metabolism in cancer cells bolsters the effectiveness of anti-programmed death ligand-1 (PD-L1) antibody. Inhibition of glutamine utilization increased PD-L1 levels in cancer cells, thereby inactivating co-cultured T cells. Under glutamine-limited conditions, reduced cellular GSH levels caused an upregulation of PD-L1 expression by impairing SERCA activity, which activates the calcium/NF-κB signaling cascade. Consequently, in tumors grown in immunocompetent mice, inhibition of glutamine metabolism decreased the antitumor activity of T cells. In combination with anti-PD-L1, however, glutamine depletion strongly promoted the antitumor efficacy of T cells in vitro and in vivo due to simultaneous increases in Fas/CD95 levels. Our results demonstrate the relevance of cancer glutamine metabolism to antitumor immunity and suggest that co-targeting of glutamine metabolism and PD-L1 represents a promising therapeutic approach.

尽管在临床上取得了巨大的成功，但免疫检查点封锁在许多患者中仍然无效。因此，迫切需要能够实现更大的抗肿瘤免疫力的联合疗法。在这里，我们报告限制癌细胞中的谷氨酰胺代谢增强了抗编程死亡配体1（PD-L1）抗体的有效性。谷氨酰胺利用的抑制增加癌细胞中PD-L1的水平，从而使共培养的T细胞失活。在谷氨酰胺有限的条件下，降低的细胞GSH水平会通过削弱SERCA活性而导致PD-L1表达上调，从而激活钙/NF-κB信号级联反应。因此，在具有免疫能力的小鼠中生长的肿瘤中，谷氨酰胺代谢的抑制降低了T细胞的抗肿瘤活性。但是，结合抗PD-L1，由于同时增加Fas / CD95水平，在体外和体内。我们的结果证明了癌症谷氨酰胺代谢与抗肿瘤免疫的相关性，并表明谷氨酰胺代谢和PD-L1共同靶向代表了一种有前途的治疗方法。