Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Colorectal cancer often features an immunosuppressive microenvironment, hindering T cell infiltration and reducing patient survival.
• Improving treatment responses in such tumors remains a significant clinical challenge.

Purpose of the Study:

• To identify druggable targets that can overcome tumor immunosuppression and enhance radiotherapy efficacy.
• To investigate the role of complement receptor C5aR1 (CD88) in colorectal cancer and its potential as a therapeutic target.

Main Methods:

• Integrated screening approach to identify cancer-specific vulnerabilities.
• Inhibition of C5aR1 and assessment of its impact on tumor radiotherapy response.
• Analysis of C5aR1 expression on tumor cells and immune cells.
• Evaluation of apoptosis induction and NF-κB pathway activation.

Main Results:

• C5aR1 was identified as a druggable target that improves radiotherapy, even in tumors with poor T cell infiltration.
• C5aR1 is expressed on malignant epithelial cells, suggesting tumor-specific functions beyond its immune role.
• C5aR1 inhibition led to increased NF-κB-dependent apoptosis specifically in tumor cells, not normal tissues.
• Targeting C5aR1 enhanced radiotherapy in immunosuppressive colorectal cancer models.

Conclusions:

• Complement gene expression increases as a stress response in irradiated tumors.
• C5aR1 targeting represents a promising strategy to improve radiotherapy outcomes, particularly in immunosuppressive colorectal cancers.
• C5aR1 plays a critical role in regulating malignant cell fate and overcoming treatment resistance.