Related Experiment Video
Updated: Jul 9, 2025
Author Spotlight: Unveiling Transmembrane Protein Family-Related Markers in Gastric Cancer and Implications for Targeted Therapies
Published on: September 15, 2023
Galectin-7 Induction by EHMT2 Inhibition Enhances Immunity in Microsatellite Stability Colorectal Cancer
Lei Sun1, Ruonian Liu1, Zong-Jian Wu2
1National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
Background & Aims:
Although immunotherapy shows substantial advancement in colorectal cancer (CRC) with microsatellite instability high, it has limited efficacy for CRC with microsatellite stability (MSS). Identifying combinations that reverse immune suppression and prime MSS tumors for current immunotherapy approaches remains an urgent need.
Methods:
An in vitro CRISPR screen was performed using coculture models of primary tumor cells and autologous immune cells from MSS CRC patients to identify epigenetic targets that could enhance immunotherapy efficacy in MSS tumors.
Results:
We revealed EHMT2, a histone methyltransferase, as a potential target for MSS CRC. EHMT2 inhibition transformed the immunosuppressive microenvironment of MSS tumors into an immunomodulatory one by altering cytokine expression, leading to T-cell-mediated cytotoxicity activation and improved responsiveness to anti-PD1 treatment. We observed galectin-7 up-regulation upon EHMT2 inhibition, which converted a "cold" MSS tumor environment into a T-cell-inflamed one. Mechanistically, CHD4 repressed galectin-7 expression by recruiting EHMT2 to form a cotranscriptional silencing complex. Galectin-7 administration enhanced anti-PD1 efficacy in MSS CRC, serving as a potent adjunct cytokine therapy.
Conclusions:
Our findings suggest that targeting the EHMT2/galectin-7 axis could provide a novel combination strategy for immunotherapy in MSS CRC.
Insights
Targeting EHMT2 in microsatellite stable colorectal cancer (MSS CRC) reverses immune suppression. This approach enhances T-cell activity and improves response to anti-PD1 immunotherapy, offering a new combination strategy.
Area of Science:
- Oncology
- Immunology
- Epigenetics
Background:
- Immunotherapy is effective for microsatellite instability-high colorectal cancer (CRC), but limited for microsatellite stability (MSS) CRC.
- There is a critical need for strategies to overcome immune suppression in MSS CRC to improve immunotherapy outcomes.
Purpose of the Study:
- To identify epigenetic targets that can enhance immunotherapy efficacy in MSS CRC.
- To explore novel combination therapies for MSS CRC.
Main Methods:
- Performed an in vitro CRISPR screen using coculture models of primary MSS CRC cells and autologous immune cells.
- Investigated the role of EHMT2 (a histone methyltransferase) and its downstream effects on the tumor microenvironment and immune cell activity.
Main Results:
- Identified EHMT2 as a target in MSS CRC. Inhibition of EHMT2 reprogrammed the immunosuppressive tumor microenvironment to an immunomodulatory one.
- EHMT2 inhibition led to increased galectin-7 expression, converting "cold" MSS tumors into a T-cell-inflamed phenotype.
- Galectin-7 administration enhanced anti-PD1 efficacy in MSS CRC, demonstrating its potential as an adjunct therapy.
Conclusions:
- Targeting the EHMT2/galectin-7 axis presents a promising novel combination strategy for enhancing immunotherapy in MSS CRC.
- This approach could overcome resistance to current immunotherapies in a significant subset of colorectal cancer patients.
