Next-Generation Chimeric Antigen Receptor Platforms for Skin Cancer Immunotherapy: Biological Rationale, Therapeutic Opportunities, and Precision Selection Strategies

Skin cancers comprise a biologically diverse group of malignancies with distinct molecular alterations, immune landscapes, and mechanisms of therapeutic resistance. Although immune checkpoint inhibitors have improved outcomes, particularly in melanoma and Merkel cell carcinoma, primary and acquired resistance remain common, underscoring the need for complementary immune-based strategies. Chimeric antigen receptor (CAR)-engineered cellular therapies redirect immune cells toward selected tumor-associated antigens. Despite the clinical success of CAR-T cells in hematological malignancies, their application to solid skin cancers remains challenging because of antigen heterogeneity, immunosuppressive tumor microenvironments, limited infiltration, and inadequate persistence. CAR engineering has expanded beyond conventional T cells, but clinical maturity varies: CAR-T therapy is established in hematological malignancies, whereas CAR-natural killer (CAR-NK) cells and CAR-macrophages (CAR-M) have entered early clinical investigation in selected cancers. CAR-dendritic cells (CAR-DC), CAR-B cells, CAR-natural killer T (CAR-NKT) cells, and CAR-γδ T cells remain predominantly preclinical or conceptual for skin cancers. Their proposed functions include cytotoxicity, innate recognition, phagocytosis, and antigen presentation, but clinical efficacy in cutaneous malignancies has not been established. This narrative review synthesizes target biology, evidence maturity, therapeutic limitations, and emerging engineering strategies. We also propose a hypothesis-generating framework for studying CAR-platform selection according to tumor subtype, antigen characteristics, immune contexture, and mechanisms of immune escape.

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