Functional Nanoplatforms Overcoming Immune Resistance in Skin Cancers: Targeted Immunomodulation, Immunogenic Cell Death, and Metabolic Remodeling.

作者：Chunyan Wang, Jun Sun, Jian-Bo Song, Sheng-Long Li, Yin-Yan Li · 发表于：Cancer Letters · 年份：2026 · DOI：10.1016/j.canlet.2026.218439 · 被引用次数：2 · 研究领域：Medicine

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 manufa...