Figueiredo CR, Kalirai H, Sacco JJ, et al. - Given the dismal outcomes and refractory nature of metastatic uveal melanoma (mUM), typically befalling in the liver, to immune checkpoint inhibitors and the poor prognosis of primary uveal melanoma (pUM) with monosomy 3 (M3), polysomy 8q and BAP1 loss, researchers here sought for the mechanisms that suppress tumor-infiltrating lymphocytes (TILs) that are present in pUM and mUM. Findings suggest a correlation of BAP1 loss with the upregulation of several genes linked with suppressive immune responses, some of which form an immune-suppressive axis, including HLA-DR, CD38, and CD74. Further, the expression of these and other markers is confirmed in single-cell analysis of pUM by mass cytometry unveiling vital functions of infiltrating immune cells in UM, most being regulatory CD8+ T lymphocytes and tumor-associated macrophages (TAMs). Transcriptomic analysis of hepatic mUM revealed similar immune profiles to pUM with BAP1 loss, including the expression of IDO1. TAMs and TILs entrapped within peritumoral fibrotic areas surrounding mUM were identified at the protein level, with exaggerated expression of IDO1, PD-L1, and β-catenin; this implies tumor-driven immune exclusion and hence the immunotherapy resistance. These findings aid in recognition of the mechanism involved in the organization of the immune response in BAP1^- mUM, which may further allow functional validation of identified biomarkers and the development of focused immunotherapeutic approaches.