Inhibition of MBTPS1 enhances antitumor immunity and potentiates anti-PD-1 immunotherapy

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Colorectal cancer (CRC) patients show limited responses to current immunotherapies.
• There is a need for strategies to enhance adaptive immune responses in CRC treatment.

Purpose of the Study:

• To identify novel therapeutic targets for enhancing immunotherapy in colorectal cancer.
• To explore the role of membrane and secreted proteins in modulating the tumor immune microenvironment.

Main Methods:

• Utilized an in vivo CRISPR-Cas9 screen targeting genes encoding membrane and secreted proteins in CRC mouse models.
• Conducted mechanistic studies to elucidate the molecular pathways affected by gene loss.
• Analyzed the impact on immune cell infiltration and anti-tumor responses.

Main Results:

• Loss of membrane-bound transcription factor site-1 protease (MBTPS1) in tumor cells significantly enhanced anti-tumor immunity.
• MBTPS1 deficiency potentiated the efficacy of anti-PD-1 therapy in CRC models.
• MBTPS1 disruption led to STAT1 stabilization, increasing expression of chemokines (CXCL9, CXCL10, CXCL11) and promoting CD8+ T cell infiltration.

Conclusions:

• MBTPS1 is a novel regulator of anti-tumor immunity in colorectal cancer, operating independently of its canonical function.
• Targeting MBTPS1 represents a promising strategy to improve immunotherapy outcomes in colorectal cancer patients.