Metabolic-immunoregulatory subtypes reveal prognostic and therapeutic insights in multiple primary lung cancer

Abstract

Background Multiple primary lung cancer (MPLC) is an increasingly recognized subtype characterized by distinct lesions with independent origins. While recent studies have profiled the immune landscape of MPLC, its tumor-intrinsic metabolic features and immunoregulatory interactions remain largely unexplored. Methods Single-cell RNA sequencing data from 11 single primary lung cancer (SPLC) tumors and 8 samples from 4 MPLC patients were analyzed using dimensionality reduction, clustering, and cell type annotation. Subtype-specific metabolic features and intercellular communication patterns were investigated through pathway enrichment and cell-cell interaction analyses. A prognostic model was constructed using Lasso-Cox regression. Immune microenvironment characteristics were assessed using deconvolution algorithms and immune-related signatures. Drug sensitivity prediction and functional assays were performed to explore potential therapeutic implications. Results This study identified a metabolically distinct malignant epithelial subpopulation enriched in MPLC tumors, characterized by upregulation of amino acid metabolism pathways and active MHC-II-mediated interactions with immunosuppressive CD4+ Treg cells and mast cells. A metabolism-based eight-gene prognostic model was developed and validated in independent lung adenocarcinoma cohorts, effectively stratifying patient survival outcomes. High-risk patients exhibited immunosuppressive tumor microenvironment features, reduced immunotherapy response potential, and distinct drug sensitivity profiles. Functional assays confirmed that key metabolic genes, spermine oxidase (SMOX) and spermine synthase (SMS), promoted tumor proliferation and invasion, accompanied by transcriptional changes in PI3K/mTOR pathway components, highlighting their potential roles in poor prognosis and therapeutic vulnerability. Conclusion This study provides a systematic characterization of malignant subpopulations in MPLC, highlighting metabolic reprogramming and immunoregulatory features that contribute to poor prognosis. These findings provide a rationale for metabolism-based prognostic stratification and highlight potential therapeutic strategies to improve clinical outcomes.