Evidence map›Paper›PMID 41121283›Full record

ArticleMolecular cancer2025

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

Shiqi Ye, Wenhao Xu, Zheqi Chen, Chuanying Zhu, Qintao Ge, Jiahe Lu, Kun Chang, Xi Tian, Aihetaimujiang Anwaier, Shuxuan Zhu and 11 more

Abstract read
In one paragraph

Article in Molecular cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

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2 · The registry

The trial behind it

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3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Review
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4 · The record

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PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

21 authors.

Shiqi Ye *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.
Wenhao Xu *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.
Zheqi Chen *State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute, Fudan University, 200433, Shanghai, China.
Chuanying Zhu *Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200092, Shanghai, China.
Qintao Ge *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.
Jiahe LuDepartment 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.
Kun ChangDepartment 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.
Xi TianDepartment 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.
Aihetaimujiang AnwaierDepartment 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.
Shuxuan ZhuDepartment 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.
Siqi ZhouDepartment 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.
Wei ZhangDepartment 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.
Yue WangDepartment 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.
Jianyuan ZhaoInstitute 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.
Lingling LiState Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute, Fudan University, 200433, Shanghai, China.
Yan ShiInstitute 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.
Tingting CaiDepartment 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.
Danfeng XuDepartment of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China. xdf12036@rjh.com.cn.
Xiangyu ZhouObstetrics & 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.
Dingwei YeDepartment 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.
Hailiang ZhangDepartment 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.

Funding

Beijing Xisike Clinical Oncology Research Foundation Y-HR2020MS-0948Beijing Xisike Clinical Oncology Research Foundation Y-Young2024-0138China Anti-Cancer Association-Hengrui PARP Nicotinamide Cancer Research Fund CETSDHRCORP252-4-021China Postdoctoral Science Foundation 2024M750538China Postdoctoral Science Foundation GZC20230500National Natural Science Foundation of China 81870285National Natural Science Foundation of China 82403377Shanghai Anticancer Association EYAS PROJECT SACA-CY23A02Shanghai Anticancer Association EYAS PROJECT SACA-CY23C04Shanghai Municipal Health Bureau 2020CXJQ03
6 · The paper itself

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.

Indexed as

Acid Anhydride HydrolasesCarcinoma, Renal CellCell Cycle ProteinsDNA-Binding ProteinsDNA Repair EnzymesKidney NeoplasmsMembrane ProteinsMRE11 Homologue ProteinNuclear ProteinsNucleotidyltransferasesAnimalsCell Line, TumorcGAS-STING Signaling PathwayCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseGene Expression Regulation, NeoplasticHumansAcid Anhydride HydrolasesCell Cycle ProteinscGAS protein, humanCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseDNA-Binding ProteinsDNA Repair EnzymesMembrane ProteinsMRE11 Homologue ProteinMRE11 protein, humanNBN protein, humanNuclear ProteinsNucleotidyltransferasesRAD50 protein, humanSTING1 protein, humanSTING ProteinACOX2cGAS-STING pathwayHomologous recombination repairMRE11-RAD50-NBS1 complexTertiary lymphoid structures

Identifiers

PMID41121283
PMCPMC12538886

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