Targeting ferroptosis pathways to overcome immunotherapy resistance in non-melanoma skin cancers

Abstract Non-melanoma skin cancers (NMSCs), including cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma, and Merkel cell carcinoma, are among the most common skin malignancies worldwide. Although immune checkpoint inhibitors (ICIs) have shown benefit in selected NMSC subtypes, primary and acquired resistance remain major barriers to durable responses. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic target because of its close links to tumor metabolism, redox balance, and the tumor microenvironment. Key ferroptosis-regulatory networks, including the glutathione peroxidase 4 (GPX4)-GSH axis, solute carrier family 7 member 11 (SLC7A11), ferroptosis suppressor protein 1 (FSP1)/coenzyme Q10 (CoQ10), acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated lipid peroxidation, and iron homeostasis, are increasingly recognized as important determinants of tumor survival and immune responsiveness. This review summarizes how major pathways associated with immune resistance, including PD-1/PD-L1 signaling, TGF-β, Wnt/β-catenin, and epigenetic regulation, influence ferroptosis sensitivity in NMSCs. We also discuss the immunological consequences of ferroptosis, particularly the role of damage-associated molecular patterns in modulating antitumor immunity. In addition, we highlight recent advances in nanomedicine-based strategies for ferroptosis induction and tumor microenvironment remodeling, including precision nanodelivery systems, stimulus-responsive nanosystems, biomimetic carriers, and combination approaches with ICIs, photothermal therapy, and photodynamic therapy. By integrating current evidence on ferroptosis, immune evasion, and advanced nanodelivery platforms, this review provides a framework for developing precision combination therapies to overcome immunotherapy resistance in NMSCs.