Mitophagy in lymph node metastasis: Mechanisms, immune consequences and therapeutic opportunities

Mitophagy, the selective autophagic clearance of damaged or superfluous mitochondria, may influence lymph node metastasis (LNM) by linking mitochondrial quality control to metabolic adaptation and immune evasion. In the lipid-rich and intermittently hypoxic lymph node niche, metastatic tumor cells often increase fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS). This metabolic shift raises mitochondrial workload and reactive oxygen species (ROS) stress, thereby increasing the demand for mitochondrial quality control. This review summarizes canonical PINK1/Parkin-dependent ubiquitin signaling and receptor/lipid-dependent mitophagy pathways, including BNIP3/NIX, FUNDC1, PHB2 and cardiolipin-mediated mechanisms. We further discuss how these pathways cooperate with DRP1-mediated mitochondrial fission, endoplasmic reticulum (ER)-mitochondria contacts and FAO/OXPHOS reprogramming during LNM. Moderate mitophagy flux may support early metastatic seeding and micrometastatic persistence by limiting ROS, preserving mitochondrial membrane potential and maintaining bioenergetic fitness. In contrast, chronic excessive mitophagy flux may restrict tumor outgrowth by depleting functional mitochondrial mass, whereas insufficient mitophagy flux may increase mitochondrial DNA leakage, cGAS-STING activation and immune visibility. We also highlight how mitophagy may attenuate mitochondrial DNA-cGAS-STING signaling, impair dendritic-cell maturation and cross-presentation, and promote a regulatory T-cell-biased immune-tolerant lymph node microenvironment. Finally, we propose a practical LN-Mitophagy Score integrating mitophagy, FAO and immune markers to guide node-targeted, stage-specific, short-course and reversible interventions, including perioperative sentinel lymph node (SLN) window trials. Key challenges include in vivo mitophagy flux quantification, safe FAO/mitochondrial modulators and immune off-target effects.