Inhibition of Dpp8/9 Activates the Nlrp1b Inflammasome
Val-boroPro (PT-100, Talabostat) has demonstrated strong anti-tumor immune activity in syngeneic cancer models, though its underlying mechanism has remained unclear. As a broad-spectrum inhibitor of post-proline-cleaving serine proteases, Val-boroPro was recently shown to induce pyroptosis—a pro-inflammatory form of programmed cell death—in monocytes and macrophages by targeting the closely related cytosolic proteases DPP8 and DPP9 (DPP8/9).
In this study, we demonstrate that DPP8/9 inhibition triggers activation of the inflammasome sensor NLRP1B, which subsequently activates pro-caspase-1 to initiate pyroptosis. These findings uncover a previously unrecognized mechanism of innate immune activation and suggest that DPP8/9 act as intracellular checkpoints that suppress NLRP1B-mediated inflammasome signaling and immune activation.