Integratively Genomic Analysis Reveals the Prognostic and Immunological Characteristics of Pyroptosis and Ferroptosis in Pancreatic Cancer for Precision Immunotherapy

The non-apoptotic cell death processes including pyroptosis and ferroptosis have been implicated in the progression and therapeutic responses of pancreatic adenocarcinoma (PAAD). However, the extent to which pyroptosis and ferroptosis influence tumor biology remains ambiguous, especially in PAAD, which is characterized with "cold" immunity. Considering the heterogeneity among different patients, it was more practical to quantify distinct cell death profiles in an individual tumor sample. Herein, we developed a pyroptosis-ferroptosis (P-F) score for PAAD patients in The Cancer Genome Atlas (TCGA) database. A high P-F score was associated with active immune phenotype, decreased genomic alterations, and significantly longer survival. Good accuracy of the P-F score in predicting overall survival (OS) was further confirmed in the TCGA-PAAD, ICGC-PACA-CA, and E-MTAB-6134 cohorts. Besides, one immunotherapy cohort (IMvigor210 dataset) has verified that patients with high P-F scores exhibited significant advantages in therapeutic responses and clinical benefits. The sensitivity to chemotherapeutics was analyzed through the Genomics of Drug Sensitivity in Cancer (GDSC), and patients with low P-F score might be more sensitive to paclitaxel and 5-fluorouracil. Collectively, the P-F score based on the systematic evaluation of cell death profiles could serve as an effective biomarker in predicting the outcomes and responses of PAAD patients to treatments with chemotherapeutic agents or immunotherapies.