2. Academic Validation
  3. ACOX2 destabilizes the MRE11-RAD50-NBS1 complex and boosts anticancer immunity via the cGAS-STING pathway in clear cell renal cell carcinoma

ACOX2 destabilizes the MRE11-RAD50-NBS1 complex and boosts anticancer immunity via the cGAS-STING pathway in clear cell renal cell carcinoma

  • Mol Cancer. 2025 Oct 21;24(1):263. doi: 10.1186/s12943-025-02420-9.
Shiqi Ye # 1 2,  Wenhao Xu # 1,  Zheqi Chen # 3,  Chuanying Zhu # 4,  Qintao Ge # 1,  Jiahe Lu 1,  Kun Chang 1,  Xi Tian 1,  Aihetaimujiang Anwaier 1,  Shuxuan Zhu 1,  Siqi Zhou 1,  Wei Zhang 1,  Yue Wang 1,  Jianyuan Zhao 5,  Lingling Li 3,  Yan Shi 5,  Tingting Cai 1,  Danfeng Xu 6,  Xiangyu Zhou 7,  Dingwei Ye 8,  Hailiang Zhang 9
Affiliations

Affiliations

  • 1 Department of Urology, Huadong Hospital, Fudan University; Department of Urology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University; Shanghai Genitourinary Cancer Institute, Fudan University, 200040, Shanghai, China.
  • 2 Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
  • 3 State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute, Fudan University, 200433, Shanghai, China.
  • 4 Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200092, Shanghai, China.
  • 5 Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 200092, Shanghai, China.
  • 6 Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China. xdf12036@rjh.com.cn.
  • 7 Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Lab of Reproduction and Development, Shanghai Key Lab of Female Reproductive Endocrine Related Diseases, Fudan University, 200433, Shanghai, China. husq04@163.com.
  • 8 Department of Urology, Huadong Hospital, Fudan University; Department of Urology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University; Shanghai Genitourinary Cancer Institute, Fudan University, 200040, Shanghai, China. dingwei_ye@fudan.edu.cn.
  • 9 Department of Urology, Huadong Hospital, Fudan University; Department of Urology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University; Shanghai Genitourinary Cancer Institute, Fudan University, 200040, Shanghai, China. zhanghl918@163.com.
  • # Contributed equally.
PMID: 41121283 DOI: 10.1186/s12943-025-02420-9
Abstract

The rapid development of ICI-based immunotherapy has ushered in a promising era for clear cell renal cell carcinoma (ccRCC). However, durable clinical responses remain limited to a subset of patients. Therefore, identifying novel predictive biomarkers and developing effective combination immunotherapies are critical for advancing personalized ccRCC management. In this study, we report that ccRCC patients exhibiting elevated ACOX2 expression may benefit from PARPi in combination with ICI. Multi-omics cohorts show ACOX2 is significantly downregulated in ccRCC and correlated with improved clinical prognosis. ACOX2 inhibits the growth of ccRCC both in vitro and in vivo. Mechanistically, ACOX2 interacts with MRE11 and inhibits the binding of MRE11 and RAD50, thereby destabilizing the MRE11-RAD50-NBS1 (MRN) complex. Furthermore, ACOX2 activates the cGAS-STING pathway, correlates with more mature tertiary lymphoid structures (TLS), and enhances CD8+ T cell infiltration and activity. Therapeutically, preclinical ccRCC models with high ACOX2 expression, including ccRCC cells, cell-derived xenograft (CDX), patient-derived Organoid (PDO), patient-derived xenograft (PDX), and immunocompetent mouse models show increased sensitivity to PARPi plus anti-PD-1 therapy. In conclusion, our findings elucidate a pivotal role of ACOX2 in inhibiting HRR and propose that PARPi, either alone or in combination with anti-PD-1 therapy, represents a promising treatment strategy for ccRCC with elevated ACOX2 expression.

Graphical Abstract:

Supplementary Information: The online version contains supplementary material available at 10.1186/s12943-025-02420-9.

Keywords

ACOX2; Homologous recombination repair; MRE11-RAD50-NBS1 complex; Tertiary lymphoid structures; cGAS-STING pathway.

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