Mitophagy acts as a core barrier to effective immunotherapy in melanoma and other skin cancersMitophagy acts as a barrier to skin cancer immunotherapy

Mitophagy serves as a pivotal metabolic-immune hub that drives immune evasion in major skin cancer subtypes including melanoma cutaneous squamous cell carcinoma and basal cell carcinoma. It acts as a core barrier to effective immunotherapy. Mitophagy activates canonical mitophagic pathways such as PINK1 Parkin and BNIP3 NIX. It extensively remodels the tumor immune microenvironment through multiple mechanisms. It skews tumor-associated macrophages toward immunosuppressive M2 polarization. It impairs antigen presentation of epidermal Langerhans cells. It induces exhaustion of CD8+ cytotoxic T lymphocytes. It also modulates pro-inflammatory cytokines including IL-1β and TNF-α. Mitophagy triggers sequential activation of NF-κB NLRP3 inflammasome and cGAS-STING signaling at the same time. It couples metabolic reprogramming and epigenetic modifications to sustain immunosuppression. A skin-cancer-specific UV-microphthalmia-associated transcription factor (MITF) regulatory axis mediates the crosstalk between mitophagy and PD-L1 expression. It generates heterogeneous and subtype-specific immune microenvironments. It further promotes resistance to immune checkpoint blockade. Mitophagy also modulates tumor antigen presentation immune checkpoint profiles and metabolic fitness of infiltrating immune cells to amplify immune evasion. This narrative review systematically delineates the multidimensional regulatory networks of mitophagy-driven immune evasion in skin cancer. It clarifies context-dependent regulatory patterns across distinct histological subtypes. It proposes precision-targeted therapeutic strategies by combining mitophagy modulation with immunotherapy. These insights provide novel mechanistic frameworks and translational targets to overcome immunotherapy resistance. They also help improve clinical outcomes for patients with advanced skin cancer.