The physiological roles and pathological implications of metabolic communication via tunneling nanotubes in immune cells

The traditional paradigm of intercellular communication is rapidly evolving. Tunneling nanotubes (TNTs) represent a distinct mode of intercellular communication, enabling the transfer of organelles, signaling molecules, and metabolic resources between spatially separated cells. Unlike soluble factor-mediated communication, TNTs establish direct physical connections that can support rapid and directional cargo transport, including mitochondrial transfer, with consequences for recipient-cell metabolism and function. In the immune system, TNT-mediated mitochondrial and other cargo transfer has been implicated in macrophage functional polarization, T-cell metabolic fitness, and natural killer (NK) cell-mediated immunity. In this review, we summarize the molecular characteristics of TNTs in immune cells, the regulation of their formation under inflammatory and metabolic stress, and the mechanisms and consequences of cargo transfer. We further examine the context-dependent nature of TNT-mediated communication, including its potential roles in host defense, tissue repair, tumor immune evasion, and pathogen dissemination. Finally, we critically evaluate transfer kinetics, quantitative scale, prevalence, in vivo evidence, and the technical limitations that currently constrain causal attribution and therapeutic translation.