MORC2-Mediated Glutamine Metabolic Remodeling Regulates Tumor-Associated Macrophage Function and Immunotherapeutic Responses in NSCLC

Abstract

Non-small cell lung cancer (NSCLC) frequently exhibits primary or acquired resistance to PD-1/PD-L1 blockade, partly because of the immunosuppressive tumor microenvironment. Tumor-associated macrophages (TAMs) are a major immune-cell population in NSCLC and contribute to tumor progression through monocyte recruitment, M2-like polarization, and impaired phagocytosis. Although blockade of the CD47–SIRPα antiphagocytic axis represents a promising TAM-directed strategy, its efficacy is limited by macrophage heterogeneity, the immunosuppressive microenvironment, and widespread CD47 expression, highlighting the need for rational combination therapies. Tumor-cell metabolic reprogramming can regulate TAM function and immune checkpoint expression, but the upstream mechanisms linking tumor metabolism to macrophage-mediated immune escape remain unclear. Our preliminary analyses identified MORC2 as a tumor-intrinsic candidate associated with TAM functional states in NSCLC. However, whether MORC2 regulates CD47 expression and macrophage dysfunction through glutamine metabolic reprogramming has not been established. In this study, we investigated the effects of MORC2 on monocyte recruitment, macrophage polarization, and phagocytosis; characterized its regulation of glutamine metabolism; examined whether glutamine-responsive mTORC1 signaling mediates MORC2-dependent CD47 expression and macrophage dysfunction; and evaluated the therapeutic effects of combining MORC2 targeting, glutamine metabolism inhibition, and CD47 blockade. Preprint notice: This is the original preprint version (v1) of this manuscript. It has not undergone peer review. Subsequent peer-reviewed versions may differ from this version.