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journal article·2026-06Open access

EEPD1 Inhibition Unleashes Antitumor Immunity in Colorectal Cancer by Activating the cGAS‐STING Pathway

Liyun Huo, Chong Wu, Xiaobo Li, Caina Ma, Jiamin Huang, Zishuo Chen, Weiling He, Tianyu Tao, Weijing Zhang

Advanced Science· Volume 13· Issue 34
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Abstract

ABSTRACT The efficacy of immunotherapy in colorectal cancer (CRC) is frequently limited by an immunosuppressive tumor microenvironment. Here, we identify exonuclease/endonuclease/phosphatase domain‐containing protein 1 (EEPD1), a gatekeeper of homologous recombination (HR) repair, as a key driver of this immune exclusion. Downregulation of EEPD1 profoundly compromises HR in CRC cells, which curtails their proliferative and metastatic capacities in vitro and in vivo. Mechanistically, EEPD1 deficiency fuels genomic instability, leading to cytosolic DNA accumulation and activation of the cGAS‐STING‐type I interferon axis. This cascade promotes dendritic cell maturation, skews macrophages toward a proinflammatory M1 phenotype, and enhances tumor‐associated antigen presentation, culminating in robust CD8 + T cell activation and cytotoxicity. Our findings elucidate a direct mechanism by which targeting EEPD1 sensitizes CRC to anti‐PD1 immunotherapy. Our work establishes EEPD1 as a promising therapeutic target to overcome immune checkpoint blockade resistance in colorectal cancer.
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Research context

OpenAlex topics: interferon and immune responses · Ubiquitin and proteasome pathways · Cancer Immunotherapy and Biomarkers

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Gastrointestinal Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong China

The Core Facilities for Medical Science at Zhongshan School of Medicine Sun Yat‐sen University Guangzhou Guangdong China

Department of Immunology and Microbiology Zhongshan School of Medicine Sun Yat‐Sen University Guangzhou Guangdong China

Department of Microbiology Zhongshan School of Medicine Sun Yat‐Sen University Guangzhou China

Dermatology Hospital Southern Medical University Guangzhou Guangdong China

Department of Gastrointestinal Surgery Xiang'an Hospital of Xiamen University School of Medicine Xiamen University Xiamen Fujian China

Cancer Research Institute School of Basic Medical Sciences Southern Medical University Guangzhou China

Department of Radiology State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou Guangdong China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Fujian Province · Basic and Applied Basic Research Foundation of Guangdong Province

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