GBP2 Enhances Anti–PD-L1 Response in Colorectal Cancer by Non-Pyroptotic Inhibition of GSDMD-Mediated YAP Activation

In this study, we investigated the biological functions of GBP2 and its impact on immune checkpoint blockade (ICB) therapy. Multi-omics analyses, in vitro assays, organoid cultures, and orthotopic tumor models revealed that GBP2 expression negatively regulates the activity and nuclear localization of Yes-associated protein (YAP), a transcriptional co-activator that drives immune evasion.

Mechanistically, GBP2 inhibits the cleavage and activation of gasdermin D (GSDMD), thereby preventing YAP nuclear translocation in a process independent of classical pyroptosis. GSDMD promotes CRC progression by enhancing YAP signaling, suppressing CXCL9/10/11 chemokine expression, and limiting CD8⁺ T cell infiltration. Loss of GBP2 activated the GSDMD–YAP axis, but targeting GSDMD restored immune cell recruitment and improved sensitivity to anti–PD-L1 therapy.