Canonical and noncanonical NF-κB signaling in uveal melanoma: mechanisms, microenvironment, and therapeutic modulation.

Abstract

<h4>Background</h4>Uveal melanoma (UM) is an aggressive intraocular malignancy with high metastatic potential to the liver and poor prognosis. The nuclear factor kappa B (NF-κB) pathway, comprising the canonical and noncanonical branches, has been involved in UM development, tumor-microenvironment communication, and drug resistance. This review consolidates the evidence for NF-κB involvement in UM pathogenesis and therapeutic target value.<h4>Methods</h4>A comprehensive search of PubMed/MEDLINE, Embase, Web of Science, Scopus, and the Cochrane CENTRAL database was performed from inception to June 2025. Studies investigating NF-κB activation, functional dependencies, genetic or microenvironmental modulators, or therapeutic interventions in UM were eligible. Included designs comprised original observational or experimental research, including mechanistic <i>in vitro</i> studies, animal models, and human tissue-based prognostic or correlative studies. English-language articles and relevant review studies addressing the research question were considered. Exclusion criteria included editorials, commentaries, conference abstracts with insufficient data, case reports lacking mechanistic insights, non-UM cancers without validated UM models, studies mentioning inflammation or NF-κB targets without direct NF-κB readouts, and those using pleiotropic inhibitors without genetic validation or pathway-specific evidence. Appropriate design-specific tools were applied to assess risk of bias.<h4>Results</h4>Canonical NF-κB signaling is mechanistically related to UM cell survival, proliferation, and migration, as shown by pharmacologic inhibition like BAY11-7082, and niclosamide and genetic modulation like microRNA-9. Noncanonical signaling is associated with invasive, immune-replenished tumors and liver metastasis yet has limited direct functional data. Deficiency in BRCA1-associated protein-1 (BAP1) and tumor necrosis factor alpha-enriched microenvironments control NF-κB activity, but there is conflicting data on the function of BAP1. Therapeutic targeting of NF-κB consistently suppresses UM phenotypes <i>in vitro</i> and <i>in vivo</i>, but pleiotropic inhibitor effects require confirmation.<h4>Conclusions</h4>NF-κB signaling, particularly the canonical branch, is required for UM malignancy, while noncanonical signaling is linked with high-risk features. Branch-specific genetic manipulations and clinically relevant models should be employed in future research to maximize therapeutic strategies.