Recent advances in the molecular genetic mechanisms and immune microenvironment of uveal melanoma

Given the therapeutic challenges posed by the unique molecular genetic mechanisms and immune-privileged microenvironment of uveal melanoma, this review aims to systematically evaluate the latest research on the molecular genetics and immune microenvironment of uveal melanoma, providing insights for translational research and the development of clinical treatment strategies. In gene therapy, a recombinant adeno-associated viral vector engineered to target the oncogenic GNAQ Q209L mutation achieved single-base-pair precision knockdown, offering a novel approach to overcoming the complex therapeutic challenges posed by downstream signaling in this pathway. Regarding tumor metastasis, BAP1 inactivation induces a low-metabolic state by inhibiting the mTORC1/p70S6K1 pathway, enabling tumor cells to adapt to nutritional stress during metastasis. Concurrently, BAP1 mutations regulate cell adhesion molecules and suppress the nuclear factor-κB pathway, collectively establishing an immunosuppressive microenvironment that drives the highly metastatic nature of uveal melanoma. The predictive value of chromosome 8q amplification was shown to be context-dependent, with high-risk subgroups exhibiting extremely poor prognosis, particularly in BAP1-mutant cases. At the epigenetic level, miR-181a-5p demonstrates therapeutic potential by inducing uveal melanoma apoptosis through targeting GNAQ and AKT3. Clinically, the bispecific T-cell redirection drug Tebentafusp has achieved a major breakthrough in metastatic uveal melanoma immunotherapy. This review systematically elucidates key driver gene mutations, chromosomal abnormalities, epigenetic alterations, and the unique immunosuppressive microenvironment of uveal melanoma, providing new insights into mechanisms of treatment resistance and guiding the development of innovative therapeutic strategies.