Abstract
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. SIGNIFICANCE: 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.