Implications of Rho GTPase signaling in cancer immunotherapy

Cancer immunotherapy, including immune checkpoint inhibitors (ICIs) and chimera-antigen receptor (CAR)-T cell therapy, has achieved substantial clinical success. However, response rates remain limited in many patients due to tumor-intrinsic immune evasion and immune cell dysfunction within the tumor microenvironment (TME). Rho family small GTPases are key signaling regulators of cytoskeletal dynamics, intracellular trafficking, transcription, and metabolism in cancers. Emerging evidence implicates Rho GTPase signaling in mediating immunotherapy efficiency through its context-dependent functions. Individual Rho GTPases modulate immunotherapy responses in tumor cells and various immune cells through actomyosin-mediated chemotaxis, cell junctions, cell polarity, and gene/epigenetic networks, among other pathways. The present review summarizes both the direct evidence linking Rho GTPases in tumor cells to immunotherapy responses and the indirect role of the selective Rho GTPase signaling network in various immune cells, with a focus on the recent progress in understanding the molecular mechanisms and associated outcomes of the ICIs and CAR-T cell therapies. We highlight current knowledge gaps at the intersection of Rho GTPase biology and cancer immunology and discuss therapeutic implications, proposing that selective modulation of specific Rho GTPase signaling pathways in tumor or TME immune cells represents a promising strategy to improve immunotherapy efficiency.