Tunneling nanotubes mediate mitochondrial homeostasis in cancer

Tumor progression is driven by cancer cells ability to establish a cellular network through tunneling nanotube-like connections (TNTs), which enable mitochondrial exchange both within the tumor cells and with the tumor microenvironment (TME). However, the effects of mitochondrial transfer between tumor and non-tumor cells, and its occurrence in vivo, remain poorly understood. In this study, we demonstrate bidirectional mitochondrial transfer: damaged mitochondria from Glioblastoma (GBM) cells trigger mitophagy in non-tumoral astrocytes (AS), while healthy mitochondria from AS enhance the metabolic activity of GBM cells. Furthermore, intravital subcellular microscopy (ISMic) in a live animal model, allowed the visualization of TNT connections with characteristics similar to those observed in vitro and supported TNT-mediated mitochondrial transfer in vivo. These findings provide critical insights into TME interactions and their contribution to cancer resilience, highlighting TNTs as a potential target for therapeutic intervention and paving the way for further research into their role in cancer.