CXCL9 drives lung adenocarcinoma progression and immunotherapy response via activation of the CXCR3/JAK1/STAT3 signaling pathway.

BACKGROUND: C-X-C Motif Chemokine Ligand 9 (CXCL9) is an immune-related chemokine implicated in tumor progression and immunotherapy response. However, its biological role and regulatory mechanisms in lung adenocarcinoma (LUAD) remain unclear. METHODS: Public immunotherapy cohorts, The Cancer Genome Atlas (TCGA) pan-cancer datasets, and single-cell RNA sequencing data were analyzed to evaluate CXCL9 expression, prognostic value, and immune associations. Functional assays, including wound healing, Transwell invasion, apoptosis analysis, qRT-PCR, and Western blotting, were performed in LUAD cell lines with CXCL9 overexpression or knockdown. Xenograft mouse models were used to assess tumor growth in vivo. Pharmacological inhibition and receptor-blocking experiments were conducted to explore the involvement of the CXCR3/janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. RESULTS: CXCL9 was significantly upregulated in programmed cell death ligand 1 (PD-L1) immunotherapy responders and associated with immune-related signaling pathways. High CXCL9 expression correlated with poor prognosis in LUAD. Functional experiments demonstrated that CXCL9 promoted LUAD cell proliferation, migration, invasion, and resistance to apoptosis both in vitro and in vivo. Mechanistically, CXCL9 activated the CXCR3/JAK1/STAT3 signaling pathway, while treatment with the JAK1/2 inhibitor Ruxolitinib effectively reversed these malignant phenotypes. CONCLUSION: Our findings identify the CXCL9-CXCR3/JAK1/STAT3 axis as a critical regulator of LUAD progression and immunotherapy response, highlighting CXCL9 as a potential prognostic biomarker and therapeutic target in LUAD.