Interplay between tunneling nanotubes and Wnt Signaling: Insights into cytoskeletal regulation and therapeutic...

Tunneling nanotubes (TNTs) are membranous structures that enable direct intercellular transfer of mitochondria, proteins, RNAs, and signaling molecules, playing key roles in tissue repair, immune coordination, and stress adaptation. Among their critical functions, TNT-mediated mitochondrial transfer rescues metabolically impaired cells, yet the regulatory mechanisms governing TNT formation and function remain incompletely understood. Recent studies highlight the Wnt signaling pathway-a conserved regulator of cell fate, polarity, and cytoskeletal remodeling-as a central modulator of TNT dynamics. Through its canonical (Wnt/β-catenin) and non-canonical (Wnt/PCP and Wnt/Ca²⁺) branches, Wnt signaling orchestrates actin filament organization, bundling, and turnover, all of which are essential for TNT biogenesis and stability. This review critically examines the mechanistic intersection between Wnt signaling and TNTs, with an emphasis on how Wnt-driven cytoskeletal remodeling supports intercellular connectivity. Beyond basic mechanistic insights, we also explore the physiological and pathological relevance of this crosstalk-including its roles in tissue regeneration, immune modulation, cancer progression, and neurodegeneration. While the Wnt-TNT axis offers therapeutic promise, its context-dependent effects demand careful consideration.