Ferroptosis is a new non-apoptotic form that regulates cell death and is mainly dependent on
iron-mediated oxidative damage and subsequent cell membrane damage. Ferroptosis may be a potential therapeutic strategy for
immunotherapy,
chemotherapy, and
radiotherapy in human
cancers. Numerous studies have analyzed ferroptosis-correlated signatures or genes, but a systematic landscape of associations among
tumor ferroptosis, clinical outcomes, tumor microenvironment, and
therapies in human
cancers is lacking. Here, we developed a relative ferroptosis level (RFL) combined with drive/suppress regulators and validated it in the Gene Expression Omnibus datasets of ferroptotic drug treatment. Based on this effective evaluation method, we classified about 7,000
tumor samples into high and low RFL groups in each
cancer type and observed that high RFL cases demonstrate favorable survival outcomes in nine
cancer types from The
Cancer Genome Atlas. Then, several RFL-correlated candidate genes that have not been reported to be ferroptosis-related were selected and experimentally validated in five
cancer cell lines using
Erastin treatment. We further showed that both immunostimulatory and immunosuppressive phenotypes were observed in high RFL
tumors, suggesting that the consideration of ferroptosis could be a potential strategy in
cancer immunotherapy. Moreover, we found that high RFL cases/cells showed responder or sensitivity to
chemotherapy and
radiotherapy. Our study provides a comprehensive molecular-level understanding of ferroptosis and may have practical implications for clinical
cancer therapies, including
immunotherapy,
chemotherapy, and
radiotherapy.