Reprogramming the immune landscape in lung cancer: spatial and metabolic contexts of c-MET signaling

The hepatocyte growth factor (HGF)/c-MET signaling axis is a central oncogenic driver in lung cancer, regulating tumor cell proliferation, epithelial–mesenchymal transition, invasion, metastasis, and therapy resistance. Increasing evidence indicates that MET signaling also appears to shape the tumor microenvironment (TME), linking tumor-intrinsic oncogenic programs with immune and metabolic regulation. Beyond its canonical tumor-promoting functions, MET may also influence tumor–immune interactions in a context-dependent manner. MET activity is spatially heterogeneous within tumors and dynamically influenced by metabolic states, stromal interactions, and co-activated oncogenic pathways. Through modulation of glycolytic reprogramming, lactate accumulation, adenosine signaling, immune checkpoint expression, and CAF-mediated microdomains, MET may contribute to the formation of localized immunosuppressive niches that facilitate immune evasion and therapeutic resistance. Emerging spatial transcriptomic analyses, single-cell profiling, and integrative metabolic assessments suggest that functional MET dependency cannot be fully captured by static genomic alterations alone. Instead, multidimensional biomarker frameworks incorporating spatial, metabolic, and immune parameters may better define biologically coherent MET-driven tumor states and inform therapeutic selection. Collectively, these insights support moving beyond a purely gene-centric view of MET targeting toward context-aware therapeutic strategies. Combinations of MET inhibition with immunomodulatory or metabolic interventions may help overcome spatially confined immune suppression and resistance mechanisms in MET-driven lung cancer.