Zhou Zhijun, Cai Yang, Yuan Hao, Chen Qun, Zhao Sophia W, Yang Jingxuan, Liu Mingyang, Arreola Alex X, Ren Yu, Xu Chao, McNally Lacey R, Bronze Michael S, Houchen Courtney W, Jiang Kuirong, Chen Wei R, Zhang Yuqing, Li Min
Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Cancer Res Commun. 2025 Aug 1;5(8):1288-1297. doi: 10.1158/2767-9764.CRC-25-0268.
Immunotherapy has revolutionized the treatment paradigms of several cancer types, yet only a subset of patients derives durable clinical benefit. Ferroptosis is a programmed cell death facilitated by iron-driven overload of lipid peroxidation. We aimed to evaluate ferroptosis activity based on tumor transcriptomic profiles to determine its predictive value for immunotherapy outcomes. We analyzed RNA sequencing data from eight independent cohorts of patients with urothelial, gastric, skin, and lung cancers treated with immune checkpoint inhibitors or adoptive T-cell therapy. A ferroptosis activity model was constructed using downstream gene expression signatures. Associations with overall survival and progression-free survival were assessed. Potential mechanisms were explored by examining immunosenescence, the IFN-γ immune response pathway, and immunogenic cell death. Ferroptosis-high tumors were associated with significantly improved overall survival and progression-free survival across multiple cancer types. Integrating ferroptosis scores with tumor mutation burden, liver metastasis status, and immune microenvironment phenotypes (inflamed, excluded, desert) enhanced patient stratification and predictive accuracy. Mechanistically, ferroptosis enhanced the immune response by promoting immunogenic cell death and attenuating immunosenescence. In conclusion, elevated ferroptosis activity correlates with improved immunotherapy outcomes, potentially through increased tumor immunogenicity and reduced immunosenescence. Ferroptosis-based biomarkers may aid in identifying patients more likely to benefit from immunotherapy.
Ferroptosis, an iron-dependent cell death process, is linked to improved immunotherapy outcomes. In this real-world study across eight cohorts, ferroptosis-high tumors showed 2 to 3 times longer survival. Mechanistically, ferroptosis enhanced immunogenicity and suppressed immunosenescence, highlighting its potential as a biomarker and therapeutic target to boost immunotherapy efficacy.
免疫疗法已经彻底改变了几种癌症类型的治疗模式，但只有一部分患者能获得持久的临床益处。铁死亡是一种由铁驱动的脂质过氧化过载所促进的程序性细胞死亡。我们旨在基于肿瘤转录组图谱评估铁死亡活性，以确定其对免疫治疗结果的预测价值。我们分析了来自八个独立队列的尿路上皮癌、胃癌、皮肤癌和肺癌患者接受免疫检查点抑制剂或过继性T细胞治疗的RNA测序数据。使用下游基因表达特征构建了铁死亡活性模型。评估了与总生存期和无进展生存期的关联。通过检查免疫衰老、IFN-γ免疫反应途径和免疫原性细胞死亡来探索潜在机制。铁死亡高的肿瘤在多种癌症类型中与显著改善的总生存期和无进展生存期相关。将铁死亡评分与肿瘤突变负担、肝转移状态和免疫微环境表型（炎症性、排除性、荒漠性）相结合可增强患者分层和预测准确性。从机制上讲，铁死亡通过促进免疫原性细胞死亡和减弱免疫衰老来增强免疫反应。总之，铁死亡活性升高与免疫治疗结果改善相关，可能是通过增加肿瘤免疫原性和减少免疫衰老实现的。基于铁死亡的生物标志物可能有助于识别更有可能从免疫治疗中获益的患者。
铁死亡，一种铁依赖性细胞死亡过程，与免疫治疗结果改善相关。在这项涵盖八个队列的真实世界研究中，铁死亡高的肿瘤显示生存期延长2至3倍。从机制上讲，铁死亡增强了免疫原性并抑制了免疫衰老，突出了其作为生物标志物和治疗靶点以提高免疫治疗疗效的潜力。
