Abstract

Background Immunotherapy has improved outcomes in non-small cell lung cancer (NSCLC), yet primary and acquired resistance remain common. Pinpointing regulators of tumor–immune crosstalk is therefore critical to enhance therapeutic efficacy. Methods We integrated multi-omics sequencing with ensemble machine-learning to nominate prognostic genes in NSCLC, followed by pathway and intercellular-signaling analyses (pseudotime analysis, GSVA, and functional enrichment). We generated shRNA-mediated FCRLB-knockdown NSCLC cell lines and performed molecular and immunological assays. A murine lung-cancer xenograft model was used to validate the role of the candidate gene in tumor progression and its impact on the tumor microenvironment (TME). Results We identified FCRLB as a key gene influencing lung cancer prognosis via transcriptomic gene screening, and elucidated its unique roles in tumor cells. FCRLB-highly expressing tumor cells exhibited high activation of the PI3K signaling and reactive oxygen species (ROS) pathways, regulated metabolic pathways such as pyrimidine metabolism and terpenoid quinone biosynthesis, and induced C-C motif chemokine ligand 2 (CCL2) production. Additionally, high FCRLB expression in NSCLC cells promoted macrophages M2 polarization, thereby further exacerbating lung cancer malignancy. Conclusions Our data identify and functionally validate FCRLB as a pro-tumor regulator in NSCLC.FCRLB regulates the secretion of multiple cytokines (including CCL2) by tumor cells via the ROS pathway and PI3K signaling pathway, thereby promoting M2 polarization of macrophages. Additionally, FCRLB exerts a positive regulatory effect on the malignant progression of NSCLC. This finding provides a potential novel target for inhibiting tumor malignant progression in NSCLC.