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

Effective cancer immunotherapy requires enhancing tumor-targeted immune responses while limiting pathological inflammation, highlighting an urgent need for single agents that can achieve this balance. Here, we reported that Betrixaban (BT), an FDA-approved Factor Xa inhibitor, functioned as a dual immunomodulator that enhanced antitumor immune responses and suppressed hyperinflammation. BT enhanced innate tumor sensing and adaptive immune responses, partly via epigenetic modulation. In mouse tumor models, BT treatment inhibited tumor growth, accompanied by increased infiltration of activated CD8+ T cells. Combining BT with immune checkpoint blockade synergistically enhanced antitumor efficacy. Additionally, BT attenuated pathological inflammation by reducing LPS-induced proinflammatory cytokine production and improving survival in a sepsis model. Mechanistically, BT induced a noncanonical, DNA-independent activation of the cGAS-STING pathway, triggering type I interferon signaling without provoking a full inflammatory cascade. These findings highlighted BT as a strategy to promote antitumor immunity while restraining inflammation, potentially improving cancer immunotherapy with reduced inflammatory toxicity.