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Peer-reviewedCC BYThe Journal of clinical investigation

TARBP2 facilitates renal cell carcinoma immune escape by suppressing 53BP1 phase separation to upregulate B7-H3.

  • Minyu Chen1,2
  • Mingjie Lin1
  • Jiangquan Zhu3
  • Kezhi Liu1
  • Guannan Shu3
  • Zhuting Tong4
  • Mi Zhou5
  • Liangmin Fu6,7,8
  • Taowei Yang1
  • Yihui Pan9
  • Xinwei Zhou1
  • Jinchen Luo1
9 more authors
  • Wuyuan Liao1,10
  • Qihao Li1
  • Lican Liao11
  • Hansen Lin1
  • Kangbo Huang12,13
  • Lizhen Zhang1
  • Wei Chen1
  • Junhang Luo1,14
  • Jiaxing Zhang11
14 affiliations
  1. 1Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  2. 2Department of Urology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
  3. 3Department of Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China.
  4. 4Department of Radiation Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
  5. 5Department of Oncology and Southwest Cancer Center, Southwest Hospital of The Third Military Medical University (Army Medical University), Chongqing, China.
  6. 6Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, China.
  7. 7Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Disease, Changsha, China.
  8. 8Uro-Oncology Institute of Central South University, Changsha, China.
  9. 9Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China.
  10. 10Department of Urology, Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen, China.
  11. 11Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  12. 12Department of Urology and.
  13. 13State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  14. 14Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{chen2026tarbp2,
  title = {{TARBP2 facilitates renal cell carcinoma immune escape by suppressing 53BP1 phase separation to upregulate B7-H3.}},
  author = {Minyu Chen and Mingjie Lin and Jiangquan Zhu and Kezhi Liu and Guannan Shu and Zhuting Tong and Mi Zhou and Liangmin Fu and Taowei Yang and Yihui Pan and Xinwei Zhou and Jinchen Luo and Wuyuan Liao and Qihao Li and Lican Liao and Hansen Lin and Kangbo Huang and Lizhen Zhang and Wei Chen and Junhang Luo and Jiaxing Zhang},
  journal = {The Journal of clinical investigation},
  year = {2026},
  month = nov,
  doi = {10.1172/jci199525},
  url = {https://europepmc.org/article/MED/42969235},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - TARBP2 facilitates renal cell carcinoma immune escape by suppressing 53BP1 phase separation to upregulate B7-H3.
AU  - Minyu Chen
AU  - Mingjie Lin
AU  - Jiangquan Zhu
AU  - Kezhi Liu
AU  - Guannan Shu
AU  - Zhuting Tong
AU  - Mi Zhou
AU  - Liangmin Fu
AU  - Taowei Yang
AU  - Yihui Pan
AU  - Xinwei Zhou
AU  - Jinchen Luo
AU  - Wuyuan Liao
AU  - Qihao Li
AU  - Lican Liao
AU  - Hansen Lin
AU  - Kangbo Huang
AU  - Lizhen Zhang
AU  - Wei Chen
AU  - Junhang Luo
AU  - Jiaxing Zhang
PY  - 2026
DA  - 2026/11/02
JO  - The Journal of clinical investigation
DO  - 10.1172/jci199525
UR  - https://europepmc.org/article/MED/42969235
AB  - 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.
SN  - 0021-9738
SN  - 1558-8238
ER  -