Abstract
Lung adenocarcinoma (LUAD) is a major contributor to cancer-related deaths, distinguished by its pronounced tumor heterogeneity and persistent challenges in overcoming drug resistance. In this study, we utilized single-cell RNA sequencing (scRNA-seq) to dissect the roles of programmed cell death (PCD) pathways, including apoptosis, necroptosis, pyroptosis, and ferroptosis, in shaping LUAD heterogeneity, immune infiltration, and prognosis. Among these, ferroptosis and pyroptosis were most significantly associated with favorable survival outcomes, highlighting their potential roles in enhancing anti-tumor immunity. Distinct PCD-related LUAD subtypes were identified, characterized by differential pathway activation and immune cell composition. Subtypes enriched with cytotoxic lymphocytes and dendritic cells demonstrated improved survival outcomes and increased potential responsiveness to immunotherapy. Drug sensitivity analysis revealed that these subtypes exhibited heightened sensitivity to targeted therapies and immune checkpoint inhibitors, suggesting opportunities for personalized treatment strategies. Our findings emphasize the interplay between PCD pathways and the tumor microenvironment, providing insights into the mechanisms underlying tumor drug resistance and immune evasion. By linking molecular and immune features to clinical outcomes, this study highlights the potential of targeting PCD pathways to enhance therapeutic efficacy and overcome resistance in LUAD. These results contribute to a growing framework for developing precise and adaptable cancer therapies tailored to specific tumor characteristics.