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

Year: 2026
Type: article
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.
DOI: 10.1172/jci199525
Authors: Minyu Chen, Mingjie Lin, Jiangquan Zhu, Kezhi Liu, Guannan Shu, Zhuting Tong, Mi Zhou, Liangmin Fu, Taowei Yang, Yihui Pan, Xinwei Zhou, Jinchen Luo, Wuyuan Liao, Qihao Li, Lican Liao, Hansen Lin, Kangbo Huang, Lizhen Zhang, Wei Chen, Junhang Luo, Jiaxing Zhang
Institutions: University of Electronic Science and Technology of China, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou Women and Children Medical Center, Guangzhou Medical University, First Affiliated Hospital of Anhui Medical University, Army Medical University, Southwest Hospital, Central South University, Second Xiangya Hospital of Central South University, Soochow University, Chinese Academy of Medical Sciences & Peking Union Medical College, Sun Yat-sen University, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China
Language: English
Subfield: Oncology
Field: Medicine
Open Access status: gold
Estimated APC paid: $5,200
OpenAlex ID: W7225046417
FWCI:
Cites: 67
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Related to: 10