Integrative analysis of the molecular mechanisms, immunological features and immunotherapy response of ferroptosis regulators across 33 cancer types

Ferroptosis is a recently described mode of cell death caused by the accumulation of intracellular iron and lipid reactive oxygen species (ROS), which play critical roles in tumorigenesis and cancer progression. However, the underlying molecular mechanisms and promising biomarkers of ferroptosis among cancers remain to be elucidated. In this study, 30 ferroptosis regulators in ferroptosis-related signaling pathways were identified and analyzed in 33 cancer types. We found transcriptomic aberrations and evaluated the prognostic value of ferroptosis regulators across 33 cancer types. Then, we predicted and validated potential transcription factors (including E2F7, KLF5 and FOXM1) and therapeutic drugs (such as cyclophosphamide, vinblastine, and gefitinib) that target ferroptosis regulators in cancer. Moreover, we explored the molecular mechanisms of ferroptosis and found that signaling pathways such as the IL-1 and IL-2 pathways are closely associated with ferroptosis. Additionally, we found that ferroptosis regulators have a close relationship with immunity-related parameters, including the immune score, immune cell infiltration level, and immune checkpoint protein level. Finally, we determined a ferroptosis score using GSVA method. We found that the ferroptosis score effectively predicted ferroptotic cell death in tumor samples. And ferroptosis score is served as an independent prognostic indicator for the incidence and recurrence of cancers. More importantly, patients with high ferroptosis scores received greater benefit from immunotherapy. We aslo created an online webserver based on the nomogram prognostic model to predict the survival in immunotherapy cohort. The reason for this outcome is partially the result of patients with a high ferroptosis rate also having high immune scores, HLA-related gene expression and immune checkpoint protein expression, such as PDL2 and TIM3. Moreover, patients with high ferroptosis scores exhibited CD8 T cell and TIL infiltration and immune-related signaling pathway enrichment. In summary, we systematically summarize the molecular characteristics, clinical relevance and immune features of ferroptosis across cancers and show that the ferroptosis score can be used as a prognostic factor and for the evaluation of immunotherapy effects.