CXCL2 is associated with IL-6/JAK2/STAT3 signaling and the immune microenvironment in lung squamous cell carcinoma

Lung squamous cell carcinoma is a major subtype of non-small cell lung cancer and remains a clinical challenge because of limited targeted therapeutic options and a high risk of recurrence after surgical resection. Identifying molecular determinants that connect tumor biology, immune regulation, and therapeutic response is essential for advancing precision medicine. In this study, we employed an integrative multi-omics strategy to investigate the biological and clinical relevance of the chemokine CXCL2 in lung squamous cell carcinoma. Transcriptomic data from The Cancer Genome Atlas and the Gene Expression Omnibus (GSE158420), as well as proteomic data from the Clinical Proteomic Tumor Analysis Consortium, were integrated to systematically analyze CXCL2 expression patterns and clinical correlations. Functional assays were performed to evaluate the effects of CXCL2 on tumor cell proliferation, migration, and invasion. Downstream regulatory mechanisms were explored using differential gene expression analysis, pathway enrichment, gene set variation analysis, and protein-level validation. Tumor immune microenvironment features were assessed using computational immune deconvolution methods, and therapeutic implications were examined through immunotherapy response prediction and drug sensitivity analysis. We found that CXCL2 was significantly downregulated in tumor tissues and cell lines and its expression was associated with gender and advanced clinical stage. In vitro functional experiments demonstrated that CXCL2 suppressed malignant phenotypes of LUSC cells, which was linked to modulation of the interleukin-6, Janus kinase 2, and signal transducer and activator of transcription 3 signaling axis. Moreover, CXCL2 expression correlated with immune-inflamed microenvironment characteristics and drug-specific therapeutic sensitivity patterns. Collectively, these findings highlight CXCL2 as a functionally and clinically relevant biomarker revealed through integrative genomics. While these results support its translational potential as a candidate biomarker for clinical risk stratification, immunotherapy response prediction, and personalized treatment guidance in LUSC, further validation in independent cohorts and mechanistic studies are warranted to confirm its clinical utility.