From energy provision to protein synthesis: Tunnelling nanotubes as mediators of intercellular metabolic cooperation in cancer

Tunnelling nanotubes (TNTs) are thin intercellular membrane structures, which enable direct cytoplasmic communication between distant cells. Since their discovery two decades ago, TNTs have been identified in numerous physiological and pathological contexts. This includes cancer, where they contribute to metabolic cooperation, stress adaptation and treatment resistance. Here we summarise the current understanding of the structural and molecular characteristics of TNTs and their cargoes, including nucleic acids, proteins, organelles, pathogens and drugs. We also discuss the cytoskeletal and motor protein machinery underlying TNT biogenesis and cargo transport. Particular attention is also given to mitochondrial transfer and its role in intercellular metabolic cooperation or parasitism, mRNA transfer and its functional effects in recipient cells, and ribosome transfer which suggests intercellular proteosynthetic cooperation. Overall, while we have learned much about TNTs since their identification a little over 20 years ago, there remain significant questions and discoveries still to be made.