Mitochondrial transfer in cancer-immune crosstalk.

Abstract

Mitochondrial transfer has emerged as a pivotal mechanism of intercellular metabolic reprogramming within the tumor microenvironment (TME), fundamentally reshaping cancer-immune crosstalk. This review provides a comprehensive synthesis of the regulatory triggers, molecular routes, and functional consequences of mitochondrial transfer in the tumor immune microenvironment. Mitochondrial exchange between tumor and immune cells occurs bidirectionally via tunneling nanotubes, extracellular vesicles, and other pathways, and is dynamically regulated by reactive oxygen species, inflammatory signaling, and metabolic stress. We delineate how this transfer exerts dual effects on antitumor immunity: tumor cells hijack functional mitochondria from T cells, macrophages, and stromal cells to fuel their proliferation and therapy resistance, while simultaneously delivering mutant mitochondria to immune cells to drive exhaustion and immune evasion. Conversely, artificial mitochondrial transfer to immune cells-including repolarization of tumor-associated macrophages via M1-derived mitochondria and metabolic augmentation of T cells and natural killer cells-demonstrates significant potential to reinvigorate antitumor immunity and overcome resistance to immune checkpoint blockade. We further discuss emerging strategies to block pro-tumoral mitochondrial hijacking through cytoskeletal inhibitors and extracellular vesicle modulators. Critical challenges for clinical translation-including precision delivery, sustained functional integration, mitochondrial DNA heteroplasmy risks, and interactions with conventional therapies-are also addressed. By integrating mechanistic insights with therapeutic innovation, this review positions mitochondrial transfer as both a targetable driver of immunosuppression and a platform for next-generation cancer immunotherapies.