State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
Department of Oral and Maxillofacial Surgery, Stomatological Center, Peking University Shenzhen Hospital, Guangdong 518036, China; Guangdong Provincial High-level Clinical Key Specialty, Guangdong 518036, China; Guangdong Province Engineering Research Center of Oral Disease Diagnosis and Treatment, Guangdong 518036, China; The Institute of Stomatology, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Guangdong 518036, China.
Cell Rep. 2024 Jul 23;43(7):114477. doi: 10.1016/j.celrep.2024.114477. Epub 2024 Jul 11.
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.
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，但许多患者并未从中受益。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 合成致死筛选，以系统地研究 PD-L1 在头颈部鳞状细胞癌 (HNSCC) 细胞中的内在功能，确定铁死亡相关基因是 PD-L1 缺陷细胞存活所必需的。铁死亡的遗传和药物诱导加速了 PD-L1 敲除细胞的死亡，这些细胞对免疫原性铁死亡也更敏感。在机制上，核 PD-L1 转录激活 SOD2 以维持氧化还原平衡。在 PD-L1 表达水平较高的 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 细胞铁死亡抗性，表明靶向 PD-L1 的内在功能可能增强治疗效果。
