The complement system contributes to the immunosuppressive microenvironment of uveal melanoma

Uveal melanoma (UM) is a rare disease, but the most common intraocular malignancy in adults, with incidence rates in Europe ranging from 1.3 to 8.6 cases per million annually. Although local tumor control is often effective, up to 50% of patients develop systemic metastases for which treatment options remain limited. Complement gene expression has been linked to poor prognosis in UM, but its role in tumor biology is still not well understood. Hypothesizing that dysregulated complement signaling fosters an immunosuppressive tumor microenvironment and promotes progression, this study for the first time investigated the role of the complement system in primary and metastatic UM. We applied an integrated approach utilizing publicly available UM bulk, single-cell RNA sequencing and proteomic data as well as immunohistochemistry of human samples, and RNA expression analysis. We also compared complement associated protein expression between primary UM (pUM) and normal ocular tissue, as well as metastatic UM (mUM) and normal liver. pUM preferentially expressed early complement components over terminal elements, with early factors demonstrating prognostic significance. High-risk tumors showed elevated secretion of C1S and C1R proteases. Fibroblasts and macrophages constituted the main sources of complement genes. mUM exhibited an expanded role for C3 relative to primary tumors. Fibroblasts were predicted to drive formation of an immunosuppressive microenvironment via RPS19–C5AR1, C3–ITGAM, and C3–C3AR interactions with macrophages and myeloid-derived suppressor cells. Trajectory analysis identified the iCAF phenotype as a transitional state between normal liver fibroblasts and mCAF, suggesting fibroblast education and involvement in pre-metastatic niche formation. Our findings identified C1S and C3 complement components as promising therapeutic targets. The availability of clinically approved complement inhibitors supports potential repurposing for high-risk pUM and mUM, offering a novel strategy to improve treatment outcomes.