A targeted MAVS fusion protein for controlled innate immune activation and antitumor therapy.

Abstract

Targeted therapies leveraging the innate immune system are emerging as promising cancer treatments. The mitochondrial antiviral signaling protein (MAVS) plays a crucial role in initiating innate immune responses, but its clinical use is limited by the risk of uncontrolled activation and systemic toxicity. To address this, we developed a novel therapeutic agent, the truncated interferon activation switch (TRIAS), combining MAVS truncates with a tumor antigen-targeting single-chain variable fragment (scFv). This design ensures antigen-dependent, controlled activation. Lentiviral delivery of TRIAS induced significant antitumor responses, including complete tumor regression in some cases. Flow cytometry (FCM) analysis further confirmed that tumor cells were the predominant population expressing the transgene. TRIAS-expressing tumor cells exhibited enhanced antitumor activity, likely due to increased cytokine release and upregulated major histocompatibility complex (MHC) expression, enabling tumor cells to function as antigen-presenting cells. This activated other immune cells, driving adaptive immune responses. Additionally, TRIAS promoted a proinflammatory shift in the tumor microenvironment (TME). In conclusion, TRIAS was validated as an innovative immunotherapeutic agent with MAVS-like immune-activating properties and tightly controlled mechanisms, offering a safer and more effective approach for clinical cancer immunotherapy.