Functional nanoplatforms overcoming immune resistance in skin cancers: Targeted immunomodulation, immunogenic cell death, and metabolic remodeling.

Skin cancers, including melanoma, cutaneous squamous cell carcinoma (cSCC), and Merkel cell carcinoma (MCC), present a fundamental paradox: high tumor immunogenicity coexists with profound immune evasion, driven by oncogenic signaling, an immunosuppressive microenvironment, metabolic dysregulation, and fibrotic stroma. Multifunctional nanoplatforms offer a systems-level strategy to overcome this multilayered resistance. They enable coordinated reprogramming of immune checkpoints and myeloid compartments, precise induction of immunogenic cell death through organelle-targeted stress or novel death pathways like cuproptosis, and synergistic use of photo-, ultrasound-, or magnetic-energy triggers. Concurrently, these platforms remodel the tumor microenvironment by scavenging immunosuppressive metabolites, exploiting lineage-specific metabolic vulnerabilities, and degrading fibrotic barriers to restore T-cell infiltration. The integration of computational intelligence-spanning AI-driven nanocarrier design, multi-omics-based patient stratification, and real-time biomarker monitoring-further empowers adaptive therapeutic strategies. By unifying biomimetic delivery, stimuli-responsive activation, and energy-coupled immunomodulation, advanced nanocarriers actively reconfigure tumor-immune crosstalk, demonstrating synergistic antitumor efficacy in preclinical models of melanoma, cSCC, and MCC. Successful clinical translation, however, requires addressing key challenges: scalable manufacturing of complex constructs, proactive management of cytokine-driven immunotoxicity, and robust biomarker-guided patient selection. The future of nano-immunotherapy lies in adaptive platforms that leverage liquid biopsy and computational modeling to dynamically counter the spatiotemporal evolution of resistance, offering a transformative paradigm for managing aggressive skin cancers.