Synthetic lethal CRISPR screen identifies a cancer cell-intrinsic role of PD-L1 in regulation of vulnerability to ferroptosis

作者：Yang-Ying-Fan Feng, Yicun Li, Haiming Liu, Rui Xu, Yu-Tong Liu, Wei Zhang, Hongyu Yang, Gang Chen · 发表于：Cell Reports · 年份：2024 · DOI：10.1016/j.celrep.2024.114477 · 被引用次数：13 · 研究领域：Ferroptosis and cancer prognosis、RNA modifications and cancer、Cancer Immunotherapy and Biomarkers

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.