Reprogramming the Melanoma Tumor Microenvironment: From Cellular Crosstalk to Cellular Immunotherapy

Melanoma is the most aggressive and rapidly metastasizing malignant neoplasm of the skin and mucous membranes, arising from melanocytes of neuroectodermal origin. Despite substantial advances in immune checkpoint inhibitors and targeted therapy, a significant proportion of patients develop primary or acquired resistance, which is largely attributable to the complex interactions between tumor cells and the tumor microenvironment (TME). This review presents a comprehensive analysis of the cellular and molecular components of the melanoma TME and their contribution to immunosuppression, tumor progression, and therapeutic resistance. The role of keratinocytes as the primary niche-forming cells in the epidermis is examined, including their reprogramming during melanomagenesis and their involvement in drug resistance. Particular attention is given to cancer-associated fibroblasts (CAFs), which orchestrate stromal remodeling, promote immune exclusion, and limit the efficacy of immunotherapy. The phenotypic and functional heterogeneity of innate and adaptive immune cells—macrophages, granulocytes, natural killer cells, dendritic cells, T and B lymphocytes—is discussed in the context of their dual role in antitumor immunity and immune escape. A detailed analysis of immune editing mechanisms, including defective antigen recognition, resistance to apoptosis, and the establishment of an immunosuppressive microenvironment, is provided. The review further summarizes the current landscape of cellular immunotherapy for melanoma. Clinically established approaches, including tumor-infiltrating lymphocytes (TILs) and CAR-T cells, are discussed with reference to completed phase II–III clinical trials, whereas emerging strategies such as CAR-macrophages and dendritic cell vaccines are presented as largely preclinical or early-phase investigational platforms. It is concluded that the melanoma TME functions as a unified immunosuppressive network rather than a collection of individual cell populations. Based on currently available comparative clinical evidence, reprogramming this network through the combination of cellular platforms with immune checkpoint inhibitors, stromal modulators, and macrophage-repolarizing agents, supported by personalized assessment of TME composition, represents a rational and actively investigated therapeutic direction.