Microneedle-Assisted Skin Delivery of Immunotherapies for Melanoma

Melanoma is one of the most aggressive and treatment-resistant skin cancers, and its long-term response to conventional therapies and systemic immune checkpoint blockade has limited efficacy because of immunosuppression induced by tumors and off-target toxicity. Transdermal microneedle (MN)-based drug delivery systems have emerged as an interesting alternative for localized, minimally invasive melanoma immunotherapy in recent years. This review is a critical analysis of the recent breakthroughs in MN-mediated immunotherapeutic models of melanoma, with a focus on the capability to: (1) regulate the tumor microenvironment (TME), (2) improve antitumor immunity, and (3) minimize the systemic adverse effects. The ability of various MN platforms, such as peptide supramolecular MNs, melanin-assisted immunotherapeutic patches, and self-locking MNs produced via micro-stereolithography, to provide sustained, spatially regulated delivery of immune checkpoint inhibitors, adjuvants, and tumor-associated antigens directly into the TME is discussed. A mechanistic understanding of immune activation cascades involving antigen-presenting cell interactions, T-cell priming, and immune memory establishment is illuminated. The review also examines strategies of synergistic combinations of MN-based immunotherapy with photothermal therapy and chemotherapeutic co-delivery to circumvent immune resistance and reprogram the immunosuppressive TME. Other important design factors, such as polymer composition, nanocarrier integration, and stimuli-responsive release mechanisms, are also discussed. There is comparative preclinical evidence that MN-based systems are superior to conventional intratumoral injections in terms of drug retention, immune cell infiltration, and tumor regression. Taken together, this review testifies to the high translational potential of microneedle technologies as highly accurate, patient-acceptable, and multifunctional vehicles of next-generation melanoma immunotherapy.