RGS protein–orchestrated microenvironment remodeling in tumor immunity: from mechanism to therapy

Regulators of G protein signaling (RGS) proteins are G protein-coupled receptor (GPCR) signaling modulators defined by a conserved RGS domain that accelerates Gα-GTP hydrolysis to attenuate signal transduction, and play context-dependent roles in regulating tumor cell proliferation, invasion, metastasis, stemness, and therapeutic resistance across various cancers. Growing evidence indicates that these molecules not only influence tumor cell malignancy but also broadly modulate diverse non-malignant populations within the tumor microenvironment, thereby contributing to microenvironmental remodeling and immunosuppression. Consequently, therapeutic targeting of RGS proteins has emerged as a promising avenue to overcome immunotherapy resistance. In this review, we outline the structural and functional landscape of RGS proteins in tumor progression, with a particular emphasis on their key mechanisms in tumor microenvironment remodeling and immunosuppressive niche formation. Furthermore, we summarize current strategies for targeting RGS proteins in cancer therapy, aiming to provide insights into the mechanisms and therapeutic opportunities of RGS proteins in tumor microenvironment.