EEPD1 Inhibition Unleashes Antitumor Immunity in Colorectal Cancer by Activating the cGAS-STING Pathway
Liyun Huo1, Chong Wu1, Xiaobo Li2
1Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
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.
Insights
Targeting EEPD1 in colorectal cancer (CRC) can overcome immune suppression. Restoring homologous recombination (HR) repair via EEPD1 enhances anti-tumor immunity and sensitizes CRC to immunotherapy.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Immunotherapy efficacy in colorectal cancer (CRC) is often hindered by an immunosuppressive tumor microenvironment.
- Immune exclusion is a significant barrier to successful anti-tumor responses in CRC.
Purpose of the Study:
- To identify novel therapeutic targets that can overcome immune exclusion in colorectal cancer.
- To investigate the role of exonuclease/endonuclease/phosphatase domain-containing protein 1 (EEPD1) in regulating the tumor microenvironment and immunotherapy response in CRC.
Main Methods:
- Investigated the role of EEPD1 in homologous recombination (HR) repair in CRC cells.
- Assessed the impact of EEPD1 downregulation on CRC cell proliferation and metastasis in vitro and in vivo.
- Analyzed the activation of the cGAS-STING-type I interferon axis and its downstream effects on immune cells.
- Evaluated the combined effect of EEPD1 targeting and anti-PD1 immunotherapy in preclinical models.
Main Results:
- Downregulation of EEPD1 compromises HR repair in CRC cells, reducing their proliferative and metastatic potential.
- EEPD1 deficiency leads to genomic instability, cytosolic DNA accumulation, and activation of the cGAS-STING-type I interferon pathway.
- This activation promotes dendritic cell maturation, M1 macrophage polarization, and enhanced antigen presentation, leading to increased CD8+ T cell activation and cytotoxicity.
- Targeting EEPD1 sensitizes CRC to anti-PD1 immunotherapy.
Conclusions:
- EEPD1 is a key regulator of immune exclusion in colorectal cancer by controlling HR repair.
- EEPD1 deficiency enhances anti-tumor immunity through the cGAS-STING pathway, sensitizing CRC to immunotherapy.
- EEPD1 represents a promising therapeutic target for overcoming resistance to immune checkpoint blockade in CRC.
