PANoptosis-Related Optimal Model (PROM): A Novel Prognostic Tool Unveiling Immune Dynamics in Lung Adenocarcinoma

Abstract

Background: PANoptosis, a recently characterized inflammatory programmed cell death modality orchestrated by the PANoptosome complex, integrates molecular mechanisms of pyroptosis, apoptosis, and necroptosis. Although this pathway potentially mediates tumor progression, its role in lung adenocarcinoma (LUAD) remains largely unexplored.

Methods: Through comprehensive single-cell transcriptomic profiling, we systematically identified critical PANoptosis-associated gene signatures. Prognostic molecular determinants were subsequently delineated via univariate Cox proportional hazards regression analysis. We constructed a PANoptosis-related optimal model (PROM) through the integration of 10 machine learning algorithms. The model was initially developed using The Cancer Genome Atlas (TCGA)-LUAD cohort and subsequently validated across six independent LUAD cohorts. Model performance was evaluated using mean concordance index. Furthermore, we conducted extensive multiomics analyses to delineate differential pathway activation patterns and immune cell infiltration profiles between PROM-stratified risk subgroups.

Results: Cellular populations exhibiting elevated PANoptosis signatures demonstrated enhanced intercellular signaling networks. PROM demonstrated superior prognostic capability across multiple validation cohorts. Receiver operating characteristic curve analyses revealed area under the curve values exceeding 0.7 across all seven cohorts, with several achieving values above 0.8, indicating robust discriminative performance. The model score exhibited significant correlation with immunological parameters. Notably, high PROM scores were associated with attenuated immune responses, suggesting an immunosuppressive tumor microenvironment. Multiomics investigations revealed significant alterations in critical oncogenic pathways and immune landscape between PROM-stratified subgroups.

Conclusion: This investigation establishes PROM as a clinically applicable prognostic tool for LUAD risk stratification. Beyond its predictive utility, PROM elucidates PANoptosis-associated immunological and biological mechanisms underlying LUAD progression. These findings provide novel mechanistic insights into LUAD pathogenesis and may inform the development of targeted therapeutic interventions and personalized treatment strategies to optimize patient outcomes.