Caveolae in cancer: mechanochemical signaling in tumor progression, immunity, and therapy

Caveolae are specialized, flask-shaped invaginations of the plasma membrane enriched in cholesterol, sphingolipids, and other membrane lipids that serve as multifunctional hubs for signal transduction, endocytosis, and mechanosensing. Their formation and functions depend on the coordinated organization of lipid microdomains, caveolins (CAV1-3), cavins (CAVIN1-4), and regulatory proteins such as EHD2 and PACSIN2, which together enable caveolae to dynamically reorganize in response to mechanical and biochemical cues. Beyond their classical functions in membrane organization, caveolae influence tumor cell proliferation, invasion, and metabolic adaptation by modulating key signaling pathways and cytoskeletal dynamics. Emerging studies suggest that caveolae contribute to tumor immune regulation by affecting antigen processing, immune cell trafficking, and the trafficking and extracellular vesicle-mediated dissemination of immune checkpoint molecules such as PD-L1. Within the tumor microenvironment, caveolae act as mechanosensitive membrane reservoirs that buffer plasma membrane tension and translate extracellular stiffness, shear stress or solid pressure into intracellular signaling responses. Through these mechanisms, caveolae may shape tumor progression, immune evasion, and responses to therapy. In this review, we synthesize current advances in caveolae biology from structural, lipid-membrane, signaling, immunological, and mechanobiological perspectives, emphasizing caveolae as integrated mechanochemical organelles rather than isolated molecular components. We discuss how caveolae couple membrane tension, lipid organization, and signaling plasticity in cancer, and we highlight emerging translational opportunities and unresolved questions relevant to tumor progression, immune regulation, and therapy.