Background Coronary heart disease (CHD) and nonsmall cell lung cancer (NSCLC) share inflammatory and immunometabolic abnormalities, yet mechanistic connections between the two diseases remain poorly defined. This study integrated multiomics analyses with functional validation to uncover shared inflammatory mediators and to delineate their roles within the NSCLC tumor microenvironment. Methods Bulk RNA‐seq datasets from CHD were analyzed for differentially expressed genes and pathway enrichment. Single‐cell RNA‐seq from NSCLC (EMTAB6149) was used to characterize cellular ecosystems, malignant subclusters, pathway activity programs, and ligand–receptor networks. Candidate mediators were evaluated across TCGA/GTEx pan‐cancer cohorts. Functional experiments included IL‐18 treatment of NSCLC cells, A2M overexpression/knockdown in cancer‐associated fibroblasts (CAFs), macrophage polarization assays, STAT3 and NF‐ κ B inhibitor studies, EMT qPCR, cytokine ELISA, cisplatin dose–response assays, and IC50 determination. Results Transcriptomic profiling revealed that immune activation, cytokine signaling, and metabolic dysregulation constitute the primary shared features between CHD and NSCLC. By integrating these findings with NSCLC single‐cell analysis, we identified IL‐18 and the A2M family as microenvironment‐enriched mediators that bridge immune activation with stromal remodeling. Functionally, IL‐18 serves as a dual driver of tumor progression. It not only directly enhances the proliferation of A549, H1299, and H1975 cells but also orchestrates an immunosuppressive niche by reprogramming macrophages. Specifically, IL‐18–stimulated macrophages exhibit a strong M2‐like polarization—characterized by the upregulation of IL10, ARG1, and CD206 and increased secretion of IL‐10 and IL‐6. Notably, conditioned medium from these reprogrammed macrophages significantly promotes NSCLC cell proliferation. These effects are receptor‐dependent, as IL‐18 neutralization or IL18R knockdown effectively abolishes the M2 phenotype. Mechanistically, this reprogramming is governed by coordinated STAT3 and NF‐ κ B activation, as inhibiting these pathways attenuates cytokine release and reverses the M2 transcriptional profile. Parallel to immune modulation, the A2M axis plays a critical role in stromal‐mediated progression. Within the tumor microenvironment, A2M overexpression in CAFs acts as a potent driver of the malignant phenotype. This stromal A2M promotes epithelial–mesenchymal transition (EMT) in tumor cells, increases growth, and markedly elevates cisplatin resistance. Conversely, A2M knockdown in CAFs reverses these protumoral effects, restoring epithelial markers and enhancing the cytotoxic efficacy of cisplatin. Conclusion Our integrative multiomics and experimental validation study identifies IL‐18 and A2M as key inflammatory–stromal mediators linking CHD‐associated immune dysregulation with NSCLC tumor progression. IL‐18 drives a protumoral microenvironment by promoting tumor cell proliferation and inducing STAT3/NF‐ κ B–dependent M2 macrophage polarization, whereas A2M‐high CAFs further enhance EMT and chemoresistance. These findings establish a mechanistic framework connecting cardiovascular inflammation with lung cancer aggressiveness and highlight IL‐18/A2M‐centered pathways as promising therapeutic targets.
Fang et al. (Thu,) studied this question.