Development and prognostic evaluation of an integrative programmed cell death index in pancreatic cancer based on multiple cell death modalities

Pancreatic cancer has exceptionally high mortality and is often clinically silent early on, with outcomes remaining poor; however, reliable tools that substantially refine prognostic stratification are still scarce. Programmed cell death (PCD) is intimately involved in tumor progression and treatment response and may provide clinically informative biomarkers. In this study, we systematically integrated genes related to 14 PCD modalities to develop a cell death index (CDI) in the TCGA cohort, followed by external validation in three independent GEO cohorts (GSE62452, GSE28735, and GSE57495). We further characterized associations between CDI-defined risk groups and the tumor microenvironment as well as predicted drug sensitivity. An eight-gene CDI signature was established and enabled effective risk stratification: patients in the high-CDI group exhibited significantly worse overall survival, and principal component analysis demonstrated clear separation between high- and low-CDI groups. Immune profiling indicated that the high-CDI group displayed an immune-cold phenotype with globally reduced immune infiltration, and drug sensitivity prediction suggested lower responsiveness to commonly used chemotherapeutic agents, including oxaliplatin and gemcitabine. Collectively, the CDI provides a practical framework for prognostic assessment and potential therapeutic stratification in pancreatic cancer, and may facilitate subsequent mechanistic studies and the development of individualized treatment strategies.