Abstract
Summary: Colon adenocarcinoma (COAD) progression involves complex interactions between tumor cell intrinsic pathways and immune evasion. Here, we show that VWA2 is markedly upregulated in COAD and correlates with poor prognosis across multiple cancer types. Using patient-derived data, cell-based assays, and in vivo models, we find that VWA2 binds β-catenin, promotes its nuclear translocation, and activates Wnt signaling. This axis drives transcription of CEMIP via TCF4, enhancing tumor cell proliferation and resistance to apoptosis, while simultaneously upregulating PD-L1 expression. The latter impairs CD8 + T cell function, revealing a dual pro-tumor role: direct growth promotion and immune suppression. These findings position VWA2 as a nodal regulator of Wnt-dependent malignant progression and immune evasion, suggesting that targeting this pathway may offer a therapeutic strategy to both curb tumor aggressiveness and restore anti-tumor immunity in COAD.