MARCH1 attenuates lung adenocarcinoma by blocking macrophage M2 polarization and cisplatin resistance through reducing SLC25A17 stability.

Cisplatin (DDP) resistance constitutes a major obstacle associated with poor prognosis in patients with lung adenocarcinoma (LUAD). Membrane-associated RING-CH finger protein 1 (MARCH1) contributed to shaping an inflamed tumor microenvironment, which is linked to chemotherapy resistance in LUAD patients. However, its role and underlying mechanisms in DDP-resistant LUAD patients remains to be elucidated. Herein, we observed that MARCH1 was downregulated in DDP-resistant lung cancer tissues, and low MARCH1 expression was correlated with poor prognosis of LUAD patients. MARCH1 overexpression enhanced DDP sensitivity, suppressed proliferation and invasion, and promoted apoptosis in DDP/A549 cells. Co-culture experiments revealed that MARCH1 overexpression suppressed the polarization of tumor-associated macrophages toward the M2 phenotype, as validated by ELISA, flow cytometry, Western blotting, and immunofluorescence staining. MARCH1 contributed to shape the tumor immune microenvironment, affecting immunostimulators, MHC molecules, chemokines, and receptors. Moreover, co-immunoprecipitation and ubiquitination experiments confirmed that MARCH1 facilitated the ubiquitination and degradation of solute carrier family 25 member 17 (SLC25A17). Rescue experiments demonstrated that overexpression of SLC25A17 attenuated the enhancement of DDP sensitivity evoked by MARCH1 reintroduction through promoting M2 macrophage polarization. Additionally, the tumor-suppressive effect of MARCH1 in LUAD was confirmed in vivo. In conclusion, our findings indicated that MARCH1 suppressed lung cancer progression by blocking macrophage M2 polarization and DDP resistance through ubiquitinating SLC25A17, thus providing a new mechanism for cisplatin resistance in LUAD.