YAP1-Driven PLCβ1 Impairs MHC-I Antigen Presentation and Limits Anti-Tumor Immunity in Gastrointestinal Cancer.

Abstract

Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet its efficacy in gastrointestinal malignancies is often limited by an immunosuppressive tumor microenvironment. In this study, we identified phospholipase C beta 1 (PLCβ1) as a central driver of pathogenesis and ICB resistance in gastrointestinal cancer. Unlike classical oncogenes, PLCβ1 promoted tumor progression by fostering immune evasion rather than directly enhancing intrinsic tumor cell survival. Mechanistically, PLCβ1 interacted with ERC1, promoting its ubiquitin-proteasomal degradation. ERC1 destabilization suppressed NF-κB-dependent transcriptional activation of MHC-I, thereby impairing antigen presentation. Upstream, the YAP1 complex served as a direct transcriptional activator of PLCβ1, and pharmacological disruption of this pathway using the YAP inhibitor effectively restored MHC-I expression. Expression PLCβ1 was associated with reduced responsiveness to immunotherapy in patients, and combining the YAP inhibitor with anti-PD-1 therapy elicited synergistic antitumor responses in both syngeneic mice and patient-derived xenografts. Collectively, these findings uncover the YAP1-PLCβ1-MHC-I axis as a critical mechanism of immune escape and propose combinatorial YAP inhibition as a promising strategy to sensitize gastrointestinal tumors to immunotherapy.