Uveal melanoma: A review of current treatment limitations and the emerging therapeutic potential of natural killer cells.

Uveal melanoma (UM) is the most common intraocular malignancy, contributing to ∼5% of all melanomas. It arises from melanocytes in the uveal tract (choroid, ciliary body, and iris) and has a specific genetic and clinical profile. Important genetic alterations shown to drive UM pathogenesis and influence prognosis include GNAQ, GNA11, BAP1, SF3B1, and EIF1AX. In addition, monosomy 3 and 8q gains are strongly linked to poor outcomes, whereas disomy 3 and 6p gains are associated with better prognosis. Approximately half of patients with UM develop metastases, most commonly to the liver, leading to high mortality. Conventional chemotherapy has shown poor efficacy, and immune checkpoint inhibitors have demonstrated only modest benefits. The immunosuppressive tumor microenvironment, particularly in the liver, further limits treatment efficacy. NK cells offer a promising avenue to treat patients owing to their ability to recognize tumor cells independent of major histocompatibility complex. However, UM employs multiple immune evasion strategies, including the upregulation of HLA-E and the secretion of immunosuppressive factors inhibiting NK cell function. Despite these barriers, preclinical studies demonstrate that activated NK cells can reduce hepatic metastases. Emerging NK cell-based therapies, such as chimeric antigen receptor-engineered NK cells and NK cell engagers, could provide an effective therapeutic strategy to treat metastatic UM, warranting further clinical investigation.