Building the bridges: molecular mechanisms of tunneling nanotube formation

Tunneling nanotubes (TNTs) are thin, actin-based conduits that provide direct cytoplasmic continuity between cells, enabling the transfer of ions, proteins, organelles, and pathogens. Although discovered nearly two decades ago, the molecular mechanisms that govern TNT biogenesis are only beginning to be resolved. Recent studies have highlighted two main formation modes: filopodia-like protrusion and cell dislodgement. Both likely involve similar molecular steps, but in different sequences. These include regulation by actin dynamics, Rho and Rab GTPases, motor proteins, and membrane-associated adaptors. Environmental stressors such as hypoxia, infection, and inflammation strongly stimulate TNT formation, underscoring their role in adaptation and survival. Understanding the molecular logic of TNT assembly is essential, as these structures influence development, immunity, cancer progression, and neurodegeneration. In this review, we summarize current knowledge of the signaling pathways, cytoskeletal regulators, and membrane remodeling events that drive TNT formation, and discuss outstanding questions.