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

ABSTRACT: Guanylate-binding protein 2 (GBP2), a member of the GTPase family, has emerged as a critical regulator of the tumor immune microenvironment (TIME) in colorectal cancer (CRC). 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. These findings uncover a previously unrecognized GBP2–GSDMD–YAP signaling pathway that shapes TIME and mediates resistance to immunotherapy. GBP2 functions as a tumor suppressor by enhancing antitumor immunity, and therapeutic strategies targeting this axis may offer new opportunities to overcome immune resistance and improve clinical outcomes in CRC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305943 | GEO | 2026/08/30

REPOSITORIES: GEO