Integrated Machine Learning Survival Framework to Decipher Diverse Cell Death Patterns for Predicting Prognosis in Lung Adenocarcinoma

Various forms of programmed cell death (PCD) collectively regulate the occurrence, development and metastasis of tumors. Nevertheless, a comprehensive analysis of the diverse types of PCD in lung adenocarcinoma (LUAD) is currently lacking. The study encompassed a total of 1481 genes associated with the regulation of 13 distinct PCD patterns. Ten machine learning algorithms were amalgamated into 101 combinations, from which the optimal algorithm was chosen to formulate an artificial intelligence-derived prognostic signature based on the average C-index across four multicenter cohorts. The established optimal cell death index (CDI) model emerged as an independent risk factor for overall survival, demonstrating robust and consistent performance. Notably, CDI exhibited significantly higher accuracy compared to traditional clinical variables and molecular features. It exhibited superior performance than other published models. By integrating CDI with relevant clinical features, a nomogram with excellent predictive performance was developed. LUAD patients with low CDI score had a higher immune modulators, TIDE scores and immune scores, indicating a better immunotherapy benefit. More importantly, we found that the regulation of antigen presentation is the crucial mechanism of PCD. SCG2 is a key molecule that inhibits the malignant progression of LUAD. CDI holds great potential as a robust and promising tool for enhancing clinical outcomes in patients with LUAD.