MS4A1 regulates M1-polarized tumor-associated macrophage infiltration, angiogenesis, and cancer progression through the HIPPO pathway in lung adenocarcinoma

Lung adenocarcinoma (LUAD) treatment remains a substantial clinical challenge, warranting a thorough investigation of the molecular mechanisms underlying tumor progression. In our study, the expression patterns and clinical implications of the macrophage M1 related gene, membrane spanning 4-domains A1 (MS4A1) were assessed using quantitative real-time PCR (RT-qPCR), western blotting, and immunohistochemistry in LUAD. A co-culture system involving LUAD cells and macrophages assessed macrophage polarization and recruitment using RT-qPCR, flow cytometry, immunofluorescence, and macrophage chemotaxis assay. Additionally, transcriptome sequencing, tube formation, and co-immunoprecipitation assays demonstrated the roles and mechanisms underlying MS4A1 in HIPPO pathway and angiogenesis in cancer progression and M1 polarization. Furthermore, the efficacy of antagonists against angiogenesis and HIPPO pathway including ivonescimab and verteporfin was assessed in MS4A1 low tumor-bearing mouse receiving immunotherapy. Results showed that the significant prognostic association of MS4A1 expression was specific to LUAD. Furthermore, MS4A1 facilitated the malignant progression of LUAD by modulating macrophage M1 polarization, migration, and angiogenesis. Mechanistically, MS4A1 interacted with Yes-associated protein to regulate macrophage polarization and cancer progression through the HIPPO pathway. In vivo experiments also demonstrated that verteporfin inhibited the in-situ tumor progression and ivonescimab enhanced the efficacy of immunotherapy in MS4A1 low tumor-bearing mouse. The MS4A1/M1 macrophage axis was identified as a crucial regulator of malignancy in LUAD, indicating MS4A1 as a promising novel therapeutic target for advanced LUAD treatment.