肿瘤免疫微环境调控虹膜黑素瘤（UM）的生长和转移。本研究旨在通过调节核因子-κB（NF-κB）信号通路，揭示BRCA1相关蛋白1（BAP1）突变对UM中肿瘤免疫微环境的可能分子机制。使用TCGA和cBioPortal数据库联合分析UM样本中高突变频率的基因。对UM患者的生存分析之后，将具有BAP1突变的UM样本进行免疫细胞浸润分析。通过GSEA筛选与突变基因相关的信号通路。随后，分析具有野生型（WT）或突变型（MUT）BAP1的选定UM细胞系中BAP1的差异表达。生物信息学分析鉴定了UM样本中12个突变基因，而只有BAP1突变与UM患者预后相关。携带BAP1突变的UM患者具有更高的免疫细胞浸润。BAP1突变抑制了NF-κB信号通路，抑制了巨噬细胞的细胞因子分泌和抗原呈递。救助实验证实，过表达NF-κB能够逆转BAP1突变对免疫抑制微环境的影响，从而抑制UM细胞的恶性表型。BAP1突变可能通过抑制NF-κB信号通路抑制巨噬细胞的细胞因子分泌和抗原呈递，诱导免疫抑制微环境，增强UM细胞的恶性表型，最终促进UM的生长和转移。© 2023. The Feinstein Institute for Medical Research.

Tumor immune microenvironment regulates the growth and metastasis of uveal melanoma (UM). This study aims to reveal the possible molecular mechanism of BRCA1-associated protein 1 (BAP1) mutations in affecting the tumor immune microenvironment in UM through mediating the nuclear factor-κB (NF-κB) signaling pathway.TCGA and cBioPortal databases jointly analyzed the genes with high mutation frequency in UM samples. Following survival analysis of UM patients, UM samples with BAP1 mutations were subjected to immune cell infiltration analysis. The signaling pathways associated with the mutated genes were screened by GSEA. Subsequently, the differential BAP1 expression was analyzed in the selected UM cell lines with wild type (WT) or mutant type (MUT) BAP1.Bioinformatics analysis identified 12 genes mutated in the UM samples, while only BAP1 mutations were related to the prognosis of UM patients. UM patients with BAP1 mutations had higher immune cell infiltration. BAP1 mutations inhibited the NF-κB signaling pathway, suppressing the cytokine secretion and antigen presentation by macrophages. Rescue experiments confirmed that overexpressed NF-κB could reverse the effect of BAP1 mutations on the immunosuppressive microenvironment, thus suppressing the malignant phenotypes of UM cells.BAP1 mutations may inhibit the NF-κB signaling pathway, repressing the cytokine secretion and antigen presentation by macrophages, which induces the immunosuppressive microenvironment, enhances the malignant phenotypes of UM cells and ultimately promotes the growth and metastasis of UM.© 2023. The Feinstein Institute for Medical Research.