Uveal melanoma (UM) is the most common primary malignant intraocular tumor in adults. Although primary UM can be effectively controlled, a significant proportion of cases (40% or more) eventually develop distant metastases, commonly in the liver. Metastatic UM remains a lethal disease with limited treatment options. The initiation of UM is typically attributed to activating mutations in GNAQ or GNA11. The elucidation of the downstream pathways such as PKC/MAPK, PI3K/AKT/mTOR, and Hippo‐YAP have provided potential therapeutic targets. Concurrent mutations in BRCA1 associated protein 1 (BAP1) or splicing factor 3b subunit 1 (SF3B1) are considered crucial for the acquisition of malignant potential. Furthermore, in preclinical studies, actionable targets associated with BAP1 loss or oncogenic mutant SF3B1 have been identified, offering promising avenues for UM treatment. This review aims to summarize the emerging targeted and epigenetic therapeutic strategies for metastatic UM carrying specific driver mutations and the potential of combining these approaches with immunotherapy, with particular focus on those in upcoming or ongoing clinical trials.

中文翻译：

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转移性葡萄膜黑色素瘤的新兴治疗策略：针对驱动突变

葡萄膜黑色素瘤（UM）是成人最常见的原发性恶性眼内肿瘤。尽管原发性 UM 可以得到有效控制，但很大一部分病例（40% 或更多）最终会发生远处转移，通常发生在肝脏。转移性 UM 仍然是一种致命疾病，治疗选择有限。UM 的启动通常归因于激活突变总纳克或者GNA11。PKC/MAPK、PI3K/AKT/mTOR 和 Hippo-YAP 等下游通路的阐明提供了潜在的治疗靶点。BRCA1 相关蛋白 1 的并发突变（BAP1) 或剪接因子 3b 亚基 1 (SF3B1）被认为对于获得恶性潜能至关重要。此外，在临床前研究中，已经确定了与 BAP1 缺失或致癌突变体 SF3B1 相关的可操作靶点，为 UM 治疗提供了有希望的途径。本综述旨在总结针对携带特定驱动突变的转移性 UM 的新兴靶向和表观遗传治疗策略，以及将这些方法与免疫疗法相结合的潜力，特别关注即将进行或正在进行的临床试验。