Abstract B025: Fusion-driven oncogenic programs shape the immune landscape in translocation renal cell carcinoma

Abstract Renal cell carcinoma (RCC) comprises a diverse group of tumors with varied molecular drivers and clinical outcomes. Despite this heterogeneity, most therapeutic approaches are based on the biology of clear cell RCC (ccRCC), the most prevalent subtype, leaving rarer subtypes such as translocation RCC (tRCC) without tailored treatments. tRCC is an aggressive and rare RCC subtype characterized by oncogenic gene fusions involving MiT/TFE transcription factors, most commonly TFE3. Standard therapies developed for ccRCC are typically less effective against tRCC, in part due to a limited understanding of its tumor-intrinsic features and tumor microenvironment (TME). To address this gap, we employed a comprehensive multi-omics approach to profile 20 tRCC tumors from 15 patients using single-nucleus RNA sequencing, single-nucleus ATAC sequencing, spatial transcriptomics, and T cell receptor sequencing. These data were compared to single-cell profiles from 32 ccRCC tumors and validated using over 1,000 bulk RNA-seq datasets. Despite a shared cell-of-origin in proximal tubule cells, tRCCs diverged markedly from ccRCC at the molecular level. tRCC tumors showed upregulation of oxidative phosphorylation, respiration, lysosomal gene programs, and a MITF-like transcriptional program, all driven by TFE3 fusions. We additionally identified six conserved oncogenic meta-programs across tRCC tumors, reflecting intratumoral heterogeneity. Among these, epithelial-mesenchymal transition (EMT) and proximal tubule identity programs were mutually exclusive and modulated by TFE3-fusion activity - higher fusion levels promoted EMT. The TME in tRCC was notably immunosuppressive, with sparse infiltration of CD8 T cells, many displaying exhausted phenotypes along with pro-tumor SPP1+ macrophages and matrix-associated fibroblasts. EMT-high tumors showed a greater association with these suppressive macrophage and stromal components, suggesting that fusion-driven EMT may contribute to shaping an immune-evasive niche. Together, our findings define tRCC as a molecularly and immunologically distinct RCC subtype, characterized by fusion-driven transcriptional programs and a highly suppressive TME. These insights help explain the poor response of tRCC to current immunotherapies and provide a foundation for rational therapeutic development, including targeting fusion-mediated pathways and reprogramming the TME to enhance immune responsiveness in tRCC. Citation Format: Prathyusha Konda, Cary Weiss, Yantong Cui, Sayed Matar, Jinyu Wang, Yasmin Nabil, Riva Deodhar, Jiao Li, Jack Horst, Sabrina Camp, Aseman Sheshdeh, Jonathan Hecht, David Einstein, Yashika Rustagi, Anwesha Nag, Aaron Thorner, Cheng-Zhong Zhang, Eliezer Van Allen, Sabina Signoretti, Toni Choueiri, Srinivas Viswanathan. Fusion-driven oncogenic programs shape the immune landscape in translocation renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr B025.