Fusion-driven oncogenic programs shape the immune landscape in translocation renal cell carcinoma
Renal cell carcinomas comprise multiple molecularly distinct cancers but most are treated empirically with therapies designed for clear cell RCC (ccRCC), the most common subtype, due to incomplete understanding of subtype-specific biology. We analyzed single-cell transcriptomes and chromatin accessibility profiles from translocation renal cell carcinoma (tRCC), an aggressive RCC defined by oncogenic TFE3 gene fusions. Unexpectedly, despite arising from a proximal tubule cell of origin similar to ccRCC, tRCCs display markedly distinct oncogenic programs and an immunosuppressive tumor microenvironment. tRCCs exhibit six conserved tumor meta-programs, including epithelial-mesenchymal transition and proximal tubule identity programs whose balance is regulated by TFE3 fusion activity. The fusion-driven EMT program drives a suppressive TME marked by progenitor-exhausted CD8+ T cells, anti-inflammatory SPP1+ macrophages, and matrix-associated fibroblasts (mCAFs). Our findings highlight unique TFE3 fusion-driven biology in tRCC, explaining its reduced immunotherapy responsiveness relative to ccRCC, and suggesting strategies for targeting fusion-driven oncogenic programs and TME reprogramming.
Authors
- Yashika Rustagi (ORCID: https://orcid.org/0000-0003-1122-941X)
- Jinyu Wang (ORCID: https://orcid.org/0000-0002-5081-8850)
- Prathyusha Konda (ORCID: https://orcid.org/0000-0002-6861-4442)
- Anwesha Nag (ORCID: https://orcid.org/0000-0002-1947-7429)
- Srinivas R. Viswanathan (ORCID: https://orcid.org/0000-0003-1856-3023)
- Eliezer M. Van Allen (ORCID: https://orcid.org/0000-0002-0201-4444)
- Cary N. Weiss (ORCID: https://orcid.org/0000-0001-7768-8956)
- Sabina Signoretti (ORCID: https://orcid.org/0000-0002-5000-9105)
- Aaron R. Thorner (ORCID: https://orcid.org/0000-0002-9160-7881)
- Toni K. Choueiri (ORCID: https://orcid.org/0000-0002-9201-3217)
- Jonathan L. Hecht (ORCID: https://orcid.org/0000-0003-4771-2585)
- Y. Cui (ORCID: https://orcid.org/0000-0003-2691-9747)
- Yasmin Nabil Laimon (ORCID: https://orcid.org/0000-0003-0848-9843)
- Maxwell D. Seager (ORCID: https://orcid.org/0009-0009-1111-6854)
- Jiao Li (ORCID: https://orcid.org/0000-0002-8027-5877)
- Cheng‐Zhong Zhang (ORCID: https://orcid.org/0000-0001-8825-7158)
- Riva Deodhar
- David J. Einstein (ORCID: https://orcid.org/0000-0001-9163-3281)
- Sayed Matar (ORCID: https://orcid.org/0000-0002-9687-2318)
- Sabrina Y. Camp
- Gabriel Roberti De Oliveira (ORCID: https://orcid.org/0009-0008-6565-7720)
- Aseman B. Sheshdeh
- Jack Horst
- Alexandra J. Wakolbinger (ORCID: https://orcid.org/0009-0000-6049-5090)
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Hadassah Medical Center (IL)
- Dana-Farber Cancer Institute (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-08-26
- DOI
- https://doi.org/10.1038/s41467-026-76858-w
- Citations
- 1
- Primary Topic
- Renal cell carcinoma treatment
- Type
- article
- Field-Weighted Citation Impact
- 5.74
Funders
- Doris Duke Charitable Foundation
- Damon Runyon Cancer Research Foundation
- National Cancer Institute
- Congressionally Directed Medical Research Programs