Uveal melanoma (UVM) is an aggressive intraocular malignancy with a high risk of metastasis but few effective therapies. However, current molecular classification systems do not completely reflect the immune-stromal interactions underlying tumor progression and immune dysfunction. Therefore, we aimed to establish a multidimensional immune ecological framework for UVM by integrating bulk and single-cell transcriptomics with analyses of immune activity, metabolic programs, regulon states, and cell-cell communication. We identified two robust immune ecological subtypes, CS1 and CS2, with markedly divergent clinical outcomes. The poor-prognosis CS1 subtype was characterized by frequent BAP1 loss, prominent IFN/STAT signaling, and a paradoxical "inflamed yet immunosuppressed" tumor microenvironment, whereas CS2 was characterized by a relatively immune-stable reference state. Through machine-learning screening across independent cohorts, we identified the transcription factor RUNX1 as a prognostic marker enriched in the CS1 subtype. Functional assays demonstrated that RUNX1 promotes UVM cell proliferation and migration, suggesting a potential role in CS1 immune ecological state. Given its enrichment in CS1, RUNX1 may be related to cytokine signaling and stromal remodeling features; however, this inference is based on subtype characteristics and requires further validation. Consistent with these subtype-specific features, CS1 tumors exhibited distinct sensitivities to dasatinib, lapatinib, paclitaxel, and cisplatin, indicating immune-state-associated therapeutic vulnerabilities. Together, these findings suggest a RUNX1-associated immunosuppressive tumor ecology in UVM and provide a conceptual framework for immune-state-guided therapeutic strategies.
Yan et al. (Wed,) studied this question.