Cellular immunotherapy in melanoma: the next frontier in cancer treatment

Therapy-resistant melanoma remains a major clinical challenge despite advances with immune checkpoint inhibitors and targeted therapies, as most patients ultimately exhibit primary or acquired resistance and progress through multiple toxic treatment lines with limited durable benefit. This resistance reflects not only T-cell dysfunction but also a profound quantitative deficit of tumor-reactive lymphocytes, compounded by myeloid- and T reg -mediated immunosuppression, impaired antigen presentation, and tumor dedifferentiation programs generating a cold tumor microenvironment. Cellular immunotherapies aim to overcome these barriers by supplying or priming new tumor-reactive repertoires while reshaping the tumor microenvironment and restoring durable immunity. Dendritic-cell vaccines safely induce broad, long-lived responses but show modest activity as monotherapy in advanced disease. Tumor-infiltrating lymphocyte therapy directly replaces the missing tumor-specific compartment and has demonstrated clinically meaningful response rates in checkpoint-refractory melanoma, though at the cost of complex, intensive manufacturing and conditioning requirements. Genetically engineered TCR-T and CAR T/CAR NK therapies provide programmable specificity but remain constrained by antigen selection, toxicity risks, and limited persistence in solid tumors. NK-cell platforms offer HLA-independent, off-the-shelf potential but require further optimization for trafficking, persistence, and resistance to suppression. Overall, rational combinations - particularly DC-priming integrated with adoptive cell therapy - represent the most promising path to durable tumor control in treatment-refractory melanoma. Overview of cellular immunotherapy platforms in melanoma and their core ex vivo manufacturing steps. (A) Dendritic cell-based vaccination uses monocyte-derived dendritic cells generated from patient blood, matured and loaded with defined tumor peptides or tumor lysate, and administered to prime antigen-specific T-cell responses in vivo. (B,C) TCR-T and CAR T-cell therapies start from peripheral blood T cells that are activated with anti-CD3 and anti-CD28, genetically modified by viral transduction or electroporation to express a tumor-specific TCR or CAR, expanded in culture, and infused after lymphodepleting chemotherapy to mediate antigen-directed tumor killing. (D) Tumor-infiltrating lymphocyte (TIL) therapy relies on surgical tumor resection, outgrowth of tumor-reactive TILs in IL-2, and rapid expansion using feeder cells and anti-CD3 prior to reinfusion after lymphodepletion. (E) NK cell-based therapy uses peripheral blood or cord blood NK cells expanded with IL-2 and IL-15 with optional feeder support and genetic engineering, including CAR expression, to generate cytotoxic products for adoptive transfer.