Betrixaban activates cGAS-STING to promote antitumor immunity without pathological inflammation

Area of Science:

• Immunology
• Pharmacology
• Oncology

Background:

• Effective cancer immunotherapy needs to balance tumor-specific immune activation with control of detrimental inflammation.
• Current strategies often struggle to achieve this dual objective with single agents.

Purpose of the Study:

• To investigate Betrixaban (BT), an FDA-approved Factor Xa inhibitor, as a potential dual immunomodulator for cancer therapy.
• To assess BT's capacity to enhance anti-tumor immunity and suppress pathological inflammation.

Main Methods:

• Utilized mouse tumor models to evaluate BT's effect on tumor growth and immune cell infiltration.
• Assessed BT's impact on innate and adaptive immune responses, including epigenetic modulation.
• Investigated BT's anti-inflammatory effects using LPS-induced cytokine production and a sepsis model.
• Explored the mechanistic basis of BT's action on the cGAS-STING pathway.

Main Results:

• BT treatment significantly inhibited tumor growth in mouse models, correlating with increased CD8+ T cell infiltration.
• BT demonstrated synergistic anti-tumor effects when combined with immune checkpoint blockade.
• BT attenuated pathological inflammation by reducing pro-inflammatory cytokine production and improving survival in sepsis.
• Mechanistically, BT activated the cGAS-STING pathway in a DNA-independent manner, inducing type I interferon signaling without excessive inflammation.

Conclusions:

• Betrixaban functions as a dual immunomodulator, enhancing anti-tumor immunity and suppressing hyperinflammation.
• BT's mechanism involves epigenetic modulation and noncanonical cGAS-STING pathway activation.
• BT represents a promising therapeutic strategy to improve cancer immunotherapy efficacy while mitigating inflammatory toxicity.