线粒体自噬驱动的肿瘤免疫逃逸多维调控及情境依赖性治疗策略

Mitophagy is a core component of MQC that maintains metabolic homeostasis and undergoes threshold-dependent dysregulation within the TME. Under hypoxia, nutrient deprivation, and metabolic stress, mitophagy not only supports tumor cell survival but also profoundly modulates antitumor immunity by reshaping immune cell metabolism, mitochondrial signaling, and epigenetic regulation.

This review integrates findings from molecular biology, metabolomics, and tumor immunology to elucidate the bidirectional immunoregulatory roles of mitophagy. Key signaling axes, including cGAS-STING, JAK-STAT, NF-κB, and HIF-1α/PD-L1, are highlighted, alongside lineage-specific effects of mitophagy in T cells, B cells, NK cells, and TAMs. Therapeutic strategies targeting PINK1/Parkin, BNIP3/FUNDC1, and OPTN-TBK1 pathways are critically discussed.

Both insufficient and excessive mitophagy disrupt immune homeostasis and promote immunosuppression through distinct mechanisms. Mitophagy deficiency leads to mtROS and mtDNA accumulation, aberrant inflammatory signaling, and functional exhaustion of T cells, B cells, and NK cells. Conversely, excessive mitophagy eliminates mitochondrial danger signals, suppresses cGAS-STING and NF-κB activation, and enhances HIF-1α/STAT3-driven PD-L1 expression. Mitophagy further enforces immune exhaustion via metabolic-epigenetic coupling.

Mitophagy is a context dependent, immune lineage specific regulatory hub linking metabolic reprogramming, immune signaling attenuation, and epigenetic remodeling. As a dynamic, tunable axis, its rational modulation may overcome tumor immune evasion and therapeutic resistance.