Single-cell epigenetic profiling reveals a tumor-intrinsic interferon response program in ccRCC tied to poor prognosis and <i>BAP1</i> loss.

Abstract

Transcriptional programs in renal cell carcinoma (RCC) have been linked to tumor heterogeneity and clinical outcomes, but analogous efforts to define chromatin programs shaping disease biology have been limited. Here, we generated single-cell ATAC-seq profiles from patients with RCC and integrated them with three previously published datasets to identify chromatin programs in tumor cells. We identified an interferon response program enriched in <i>BAP1</i>-mutant tumors, and, in bulk ATAC-seq cohorts with linked clinical data, this program was associated with poor prognosis. Mechanistic analyses in isogenic models suggested that <i>BAP1</i> loss induces a tumor-intrinsic interferon response, with dysregulated endogenous retroviruses as a potential upstream trigger. We further characterized the <i>BAP1</i> mutation-associated tumor microenvironment across single-cell, bulk, and multiplex immunofluorescence data, identifying features of both inflammation and immune evasion. Together, our findings nominate tumor-intrinsic interferon signaling as a candidate driver of <i>BAP1</i>-associated aggressiveness in RCC and highlight immune evasion pathways as potential therapeutic targets.