Activated stimulator of interferon genes induces remodeling of myeloid-derived suppressor cells to inhibit lung adenocarcinoma progression

Stimulator of interferon genes (STING) signaling mediates antitumor immunity. However, its regulatory impact on myeloid-derived suppressor cells (MDSCs) in lung adenocarcinoma (LUAD) remains elusive. This study investigated the effects of STING signaling on MDSC accumulation and function and evaluated the potential of STING reactivation to remodel the tumor microenvironment. STING expression and immunological correlations were analyzed using public LUAD cohorts and validated in clinical samples and Lewis lung carcinoma mouse models. MDSC subsets and intrinsic STING activation were quantified via flow cytometry, multiplex immunofluorescence, and western blotting. The therapeutic efficacy of the STING agonist cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) was assessed in tumor-bearing mice. STING expression was downregulated in LUAD and correlated with increased MDSC infiltration and poor prognosis. Clinical data revealed elevated peripheral MDSCs characterized by diminished intrinsic STING phosphorylation. In the Lewis lung carcinoma model, systemic administration of cGAMP inhibited tumor growth and reduced MDSC infiltration. Mechanistically, cGAMP restored STING pathway activation within MDSCs, downregulating arginase-1 and attenuating their suppressive capacity. This phenotypic shift was accompanied by increased systemic interferon-β levels and decreased transforming growth factor-beta and prostaglandin E₂ levels. STING deficiency drives MDSC-mediated immunosuppression in LUAD. Systemic pharmacological STING activation alleviates this immunosuppression by concurrently restoring MDSC-intrinsic signaling and reducing systemic immunosuppressive factors, offering a strategy to remodel the tumor microenvironment and overcome immune resistance.