TARBP2 facilitates renal cell carcinoma immune escape by suppressing 53BP1 phase separation to upregulate B7-H3
Renal cell carcinoma (RCC) harbors an immunosuppressive tumor microenvironment that facilitates immune evasion and resistance to immune checkpoint blockade (ICB). However, the factors driving immune escape in RCC remain incompletely understood. In this study, transactivation response RNA-binding protein 2 (TARBP2) was identified as a critical regulator of the immune checkpoint molecule B7-H3. Elevated TARBP2 expression was associated with poor prognosis and ICB resistance in patients with RCC. Functionally, TARBP2 in RCC cells suppressed the intratumoral accumulation and cytotoxicity of T cells, particularly NK cells, thereby promoting immune escape. Mechanistically, nuclear TARBP2 interacted with p53-binding protein 1 (53BP1), inhibiting 53BP1 phase separation and subsequent p53 activation, thereby augmenting B7-H3 transcription. Furthermore, TARBP2 inhibition significantly enhanced ICB efficacy when combined with adoptive NK cell therapy. Collectively, these findings establish TARBP2 as a key mediator of immune evasion in RCC and a promising therapeutic target for overcoming ICB resistance.
Authors
- Zhuting Tong (ORCID: https://orcid.org/0000-0002-5915-7331)
- Guannan Shu (ORCID: https://orcid.org/0000-0003-4075-3181)
- Wuyuan Liao (ORCID: https://orcid.org/0009-0003-1270-569X)
- Hansen Lin
- Jiangquan Zhu
- Minyu Chen
- Xinwei Zhou
- Jinchen Luo
- Yihui Pan
- Lican Liao
- Liangmin Fu
- Mingjie Lin
- Taowei Yang
- Wei Chen
- Kangbo Huang
- Mi Zhou
- Junhang Luo
- Kezhi Liu
- Jiaxing Zhang
- Lizhen Zhang
- Qihao Li
Institutions
- Central South University (CN)
- University of Electronic Science and Technology of China (CN)
- Army Medical University (CN)
- Sun Yat-sen University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Soochow University (CN)
- Guangzhou Women and Children Medical Center (CN)
- Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Southwest Hospital (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
- Sun Yat-sen University Cancer Center (CN)
- Second Xiangya Hospital of Central South University (CN)
- State Key Laboratory of Oncology in South China (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2026-11-01
- DOI
- https://doi.org/10.1172/jci199525
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Natural Science Foundation of Guangdong Province
- Guangdong Medical Research Foundation
- Natural Science Foundation of Jiangsu Province