Riluzole Enhancing Anti-PD-1 Efficacy by Activating cGAS/STING Signaling in Colorectal Cancer

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Colorectal cancer is a leading cause of cancer death.
• Current immunotherapies like anti-PD-1/PD-L1 have limited efficacy in many patients.
• Novel therapeutic strategies are needed to improve colorectal cancer treatment outcomes.

Purpose of the Study:

• To investigate the anti-tumor effects of riluzole in colorectal cancer.
• To elucidate the underlying molecular mechanisms of riluzole's action.
• To evaluate the potential of riluzole in combination with immune checkpoint inhibitors.

Main Methods:

• Utilized syngeneic immune-competent mouse models of colon cancer.
• Administered riluzole and assessed tumor growth and intratumoral CD8+ T cell infiltration.
• Investigated the role of the cGAS/STING pathway and ATM in riluzole's mechanism of action.
• Combined riluzole with anti-PD-1 therapy to evaluate synergistic effects.

Main Results:

• Riluzole suppressed tumor growth and increased intratumoral CD8+ T cells in a CD8+ T cell-dependent manner.
• Riluzole activated the cGAS/STING pathway in colon cancer cells, upregulating IFNβ and CXCL10.
• Riluzole's effects were dependent on cGAS/STING activation and involved an ATM-mediated DNA damage response.
• Combination therapy with riluzole and anti-PD-1 demonstrated enhanced anti-tumor efficacy compared to single agents.

Conclusions:

• Riluzole activates tumor cell-intrinsic cGAS/STING innate immune responses.
• Riluzole enhances CD8+ T cell infiltration and tumor suppression.
• Riluzole shows promise as a sensitizer for anti-PD-1/PD-L1 therapies in colorectal cancer.