Authors
Yu Meng, Qian Zhou, Deze Zhao, Hui Su, Jiayuan Le, Daishi Li, Lei Yao, Ziyu Guo, Yixiao Xiong, Yuming Sun, Xiaowei Liang, Furong Zeng, Guangtong Deng, Xiang Chen
Published in
Cancer research. Aug 06, 2026. Epub Aug 06, 2026.
Abstract
Induction of ferroptosis is a potential strategy for treating cancer and improving the efficacy of immunotherapy. Ferroptosis is driven by excessive peroxidation of polyunsaturated fatty acid-containing phospholipids, suggesting that microenvironmental lipid metabolites may regulate ferroptotic sensitivity. By integrating single-cell and bulk transcriptomics from immunotherapy cohorts, we identified the prostaglandin (PG) pathway as closely associated with tumor ferroptosis and therapeutic efficacy. Further screening revealed PGF2α as a potent endogenous ferroptosis sensitizer. Mechanistically, microenvironmental PGF2α bound to ferroptosis suppressor protein 1 (FSP1) at alanine 295 (A295) and inhibited its enzymatic activity, leading to lipid peroxidation accumulation upon ferroptotic stimuli. Preclinically, PGF2α supplementation or FSP1 ablation enhanced tumoral ferroptosis, potentiated CD8+ T cell-mediated immunity, and suppressed tumor progression in immunocompetent mice. Moreover, PGF2α improved immunotherapy efficacy across multiple mouse models, including subcutaneous allografts, Braf/Pten-driven spontaneous melanoma, and humanized mice. Clinically, a high PGF2α activity-related transcriptomic signature correlated with elevated ferroptosis and improved patient survival. Collectively, these findings establish PGF2α as a pro-ferroptotic metabolite and propose that targeting the PGF2α/FSP1 axis may offer an effective cancer immunotherapeutic strategy.
PMID:
42561142
Bibliographic data and abstract were imported from PubMed on 07 Aug 2026.
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