Harnessing dendritic cells (DCs) for melanoma immunotherapy: From basic biology to clinical strategies.

Melanoma, as an immunogenic skin cancer, is an area of great interest in cancer immunotherapy. Immune checkpoint inhibitors (ICIs) have resulted in improved clinical outcomes in selected patients, but resistance or relapsing disease remains a problem. Dendritic cells (DCs) have the potential to enhance antitumor immunity since they are the most potent antigen-presenting cells and can prime and activate tumor-specific T cells. Recent advancements in single-cell technologies have enabled us to characterize tumor-infiltrating DC subsets (conventional type 1 (cDC1s) and cDC2s, plasmacytoid (pDCs), monocyte-derived (moDCs), as well as potentially novel subsets like DC3s) entirely and characterize their distinct roles in promoting melanoma development, evading immune surveillance, and/or their ability to respond to therapy. DCs can capture, process, and present antigens to activate and regulate T-cell-mediated immune responses, with T-cell immunity needed to control melanoma. Consequently, Next-generation DC-based immunotherapy approaches are being examined. These approaches involve vaccines that utilize naturally circulating DC subsets (ie, CD1c⁺ mDCs, activated pDCs) as well as DCs charged with tumor-specific neoantigens or mRNA, and approaches containing toll-like receptor (TLR) ligands, STING pathway agonists, nanoparticles, and oncolytic viruses to enhance DC maturation and antigen presentation. Furthermore, DC will be combined with treatments including ICIs, adoptive T cell therapy, or chemotherapy to induce enhanced synergistic immune reactions. In this review, we summarize the DC subset functions in melanoma, the underlying mechanisms of DC dysfunction in the tumor microenvironment, and the most recent updates on next-generation DC-based therapies. We also highlight the need for clinical translation and determining barriers and challenges in the personalization of melanoma vaccines and even combination treatment with pre-existing therapies that consider the potential of DC biology.