Targeting CTGF overcomes resistance to CSF1R inhibitors by preventing CAF activation in colorectal cancer

Area of Science:

• Oncology
• Immunology
• Cancer Biology

Background:

• Colorectal cancer (CRC) immunotherapy resistance is a major challenge.
• Targeting colony-stimulating factor 1 receptor (CSF1R) to deplete tumor-associated macrophages (TAMs) is a potential strategy against CRC.
• Resistance to CSF1R inhibitors limits their clinical effectiveness.

Purpose of the Study:

• To investigate the mechanisms of resistance to CSF1R inhibitors in colorectal cancer.
• To identify novel therapeutic targets to enhance CSF1R inhibitor efficacy.
• To evaluate combination therapies for overcoming immunotherapy resistance in CRC.

Main Methods:

• Imaging mass cytometry (IMC) was used to analyze the tumor microenvironment.
• Pharmacological inhibition of CSF1R (PLX3397) and anti-CTGF therapy were employed in preclinical models.
• Combination therapy including CSF1R inhibitor, anti-CTGF, and checkpoint immunotherapy was assessed for anti-tumor activity.

Main Results:

• CSF1R inhibition reduced TAMs but did not suppress tumor growth.
• PLX3397 activated cancer-associated fibroblasts (CAFs) by inducing the PI3K/AKT pathway and CTGF release.
• CSF1R inhibition impaired T cell infiltration and function.
• Anti-CTGF therapy restored CSF1R inhibitor efficacy.
• Combination therapy of CSF1R inhibitor, anti-CTGF, and checkpoint immunotherapy led to complete tumor regression in vivo.

Conclusions:

• CSF1R inhibitors can paradoxically promote CAF activation and immunosuppression in CRC.
• Combined targeting of CSF1R, CTGF, and immune checkpoints offers a promising strategy to overcome resistance and achieve complete tumor regression in colorectal cancer.