Emerging Roles of Cytoneme-Mediated Signaling in Cancer

Intercellular communication across cancer cells and the tumor microenvironment (TME) is essential for tumor growth, invasion, metastasis, and therapeutic resistance. Traditionally, these interactions have been viewed through the lens of diffusible signaling molecules and extracellular vesicles. However, growing evidence supports an additional paradigm in which specialized cytoskeleton-based membrane extensions, like tunneling nanotubes (TNTs), tumor microtubes (TMs), and cytonemes, mediate direct, contact-dependent communication between cells. This review examines the emerging roles of these cellular extensions in cancer biology, with a particular emphasis on cytonemes, long specialized signaling filopodia that facilitate transport and reception of signaling ligands and receptors. Cytonemes are interwoven with developmental signaling pathways, which are frequently reactivated in cancer, promoting tumor progression. We discuss cytoneme pathology in cancer, with specific examples in growth, stemness, invasion, and microenvironmental remodeling. These extensions represent an unexplored facet of tumor biology and a promising avenue for therapeutic intervention.