Mitochondria regulate energy metabolism, redox balance, cell survival, and innate immune signaling. Neutrophils, the most abundant circulating innate immune effector cells, play an essential role in reshaping the tumor microenvironment and can exhibit both anti-tumor and tumor-supporting behaviors. Although mitochondrial processes are increasingly recognized as key drivers of neutrophil functional diversity and neutrophil-tumor cell communication, a systematic synthesis centered on mitochondria remains limited. The review opens with an overview of defining features of mitochondrial biology, including fission and fusion dynamics, oxidative stress responses, calcium balance, apoptosis-related pathways, and mitochondrial damage signals that influence immune activation. Mitochondria-dependent programs supporting neutrophil survival, lifespan control, and physiological defense functions are then outlined to show how subcellular metabolism shapes innate effector activity. The focus subsequently shifts to mitochondrial contributions in tumor-supportive interactions between neutrophils and tumor cells, highlighting the capacity of mitochondrial signals from both sides to reinforce tumor-promoting neutrophil traits, tumor cell aggressiveness, and bidirectional crosstalk. Emerging strategies capable of redirecting neutrophil mitochondria toward anti-tumor phenotypes are finally summarized, including stimulation of mitochondrial biogenesis, delivery of mitochondrial-targeted proteins to enhance neutrophil-driven immunity, dual disruption of extracellular traps and tumor mitochondria to break tumor-supportive feedback, and modulation of mitochondrial quality-control and oxidative signaling to rebalance tumor-supportive neutrophils. A mitochondria-centered subcellular perspective provides a more cohesive framework for understanding neutrophil-tumor communication and may help inform the development of subcellularly targeted cancer therapies.
Shen et al. (Sat,) studied this question.