Abstract The tumor microenvironment (TME) is a dynamic and highly interactive ecosystem that fuels cancer progression through coordinated cellular crosstalk. Recent studies have uncovered intercellular mitochondrial transfer as a critical adaptive mechanism within this niche. Here, we synthesize current evidence supporting a paradigm in which mitochondria function as “shared organelles”, whose bidirectional trafficking reshapes tumor and immune cell states. We discuss the mechanisms by which cancer cells acquire functional mitochondria from stromal compartments to enhance bioenergetic fitness, metabolic plasticity, and resistance to therapy. Conversely, we highlight the transfer of damaged or dysfunctional mitochondria from tumor cells to immune populations, a process that contributes to immune suppression and impaired anti-tumor responses. We further delineate the molecular and cellular networks regulating mitochondrial exchange, including tunneling nanotubes, extracellular vesicles, and cytoskeletal dynamics. Finally, we evaluate emerging therapeutic strategies aimed at disrupting mitochondrial trafficking and reprogramming TME metabolism. Collectively, this review positions mitochondrial transfer as a fundamental driver of tumor progression and a promising, yet underexplored, target for cancer therapy.
Yang et al. (Thu,) studied this question.