尽管程序性细胞死亡 1 (PD-1)/程序性死亡配体 1 (PD-L1) 抑制在肿瘤治疗中取得了成功，但许多患者并未受益。这种失败可能归因于 PD-L1 的内在功能。我们进行了全基因组 CRISPR 合成致死性筛选，系统地探索 PD-L1 在头颈鳞状细胞癌 (HNSCC) 细胞中的内在功能，确定铁死亡相关基因对于 PD-L1 缺陷细胞的生存至关重要。铁死亡的遗传和药理学诱导会加速 PD-L1 敲除细胞的细胞死亡，这些细胞也更容易受到免疫原性铁死亡的影响。从机制上讲，核 PD-L1 转录激活 SOD2 以维持氧化还原稳态。在 PD-L1 表达较高的 HNSCC 患者中观察到较低的活性氧 (ROS) 和铁死亡。我们的研究表明，PD-L1 通过激活 SOD2 介导的抗氧化途径赋予 HNSCC 细胞铁死亡抵抗力，这表明针对 PD-L1 的内在功能可以增强治疗效果。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Despite the success of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibition in tumor therapy, many patients do not benefit. This failure may be attributed to the intrinsic functions of PD-L1. We perform a genome-wide CRISPR synthetic lethality screen to systematically explore the intrinsic functions of PD-L1 in head and neck squamous cell carcinoma (HNSCC) cells, identifying ferroptosis-related genes as essential for the viability of PD-L1-deficient cells. Genetic and pharmacological induction of ferroptosis accelerates cell death in PD-L1 knockout cells, which are also more susceptible to immunogenic ferroptosis. Mechanistically, nuclear PD-L1 transcriptionally activates SOD2 to maintain redox homeostasis. Lower reactive oxygen species (ROS) and ferroptosis are observed in patients with HNSCC who have higher PD-L1 expression. Our study illustrates that PD-L1 confers ferroptosis resistance in HNSCC cells by activating the SOD2-mediated antioxidant pathway, suggesting that targeting the intrinsic functions of PD-L1 could enhance therapeutic efficacy.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.