Identification and verification of a combined ferroptosis- and pyroptosis-related signature for a prognostic classifier and immunosuppressive targets in colorectal cancer

Background and study aims: Ferroptosis and pyroptosis, two forms of cell death, are increasingly reported for their pivotal roles in cancer biology. However, the understanding of the combined ferroptosis-pyroptosis (FPtosis)related gene signature in colorectal cancer (CRC) remains limited. Material and methods: We conducted a comprehensive investigation of the FPtosis-related signature in CRC. Data integration from both the training and validation cohorts was performed. The FPtosis-related signature was established. We evaluated the prognostic significance of the signature through Kaplan-Meier analysis, as well as univariate and multivariate Cox regression models. Functional analyses were conducted to explore the underlying biological mechanisms. Additionally, we analyzed the correlations between the FPtosis-related signature, immune infiltration, and immune checkpoint blockade (ICB) immunotherapy. Results: The FPtosis-related signature demonstrated significant prognostic potential and can serve as an independent biomarker for predicting outcomes. The signature showed correlations with advanced tumor stage, invasion depth, lymph node metastasis, and distant metastasis. Subgroup analyses revealed the valuable predictive role of the FPtosis-related signature in predicting survival across different clinical subgroups, including age, gender, tumor stage, invasion depth, lymph node metastasis status, and distant metastasis status. Moreover, the signature exhibited positive associations with inflammation and the infiltration of diverse immune cells, such as neutrophils, M0 and M2 macrophages, and regulatory T cells (Tregs). In microsatellite instable (MSI) CRC, the expression of most ICB genes was higher in the high-FPtosis group compared to the low-FPtosis group. Conclusion: The FPtosis signature can effectively predict the prognosis of CRC and had the potential to improve the development of innovative therapeutic strategies.