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posted on 2025-03-04, 08:21 authored by Jiazheng Sun, Pin Wang, Ziying Yi, Yushen Wu, Yuxian Wei, Huiying Fang, Daqiang Song, Yuru Chen, Huimin Du, Jing Huang, Qin Li, Dejuan Yang, Guosheng Ren, Hongzhong Li Figure S3 WNT7A blockage inhibits tumor growth and enhances anti-tumor immunity.
Funding
National Natural Science Foundation of China (NSFC)
Nature Science Foundation of CHongqing
Chongqing Medical Scientific Research Project/Joint Project of Chongqing Health Commission and Science and Technology Bureau
Chongqing Graduate Tutor Team Construction Project, Chongqing Education Commission Foundation
CQMU Program for Youth Innovation in Future Medicine
History
ARTICLE ABSTRACT
The limited infiltration of CD8+ T cells in tumors hampers the effectiveness of T cell–based immunotherapy, yet the mechanisms that limit tumor infiltration by CD8+ T cells remain unclear. Through bulk RNA sequencing of human tumors, we identified a strong correlation between WNT7A expression and reduced CD8+ T-cell infiltration. Further investigation demonstrated that inhibiting WNT7A substantially enhanced MHC-I expression on tumor cells. Mechanistically, WNT7A inhibition inactivated the Wnt/β-catenin signaling pathway and thus resulted in reduced physical interaction between β-catenin and p65 in the cytoplasm, which increased the nuclear translocation of p65 and activated the NF-κB pathway, ultimately promoting the transcription of genes encoding MHC-I molecules. We found that our lead compound, 1365-0109, disrupted the protein–protein interaction between WNT7A and its receptor FZD5, resulting in the upregulation of MHC-I expression. In murine tumor models, both genetic and pharmaceutical suppression of WNT7A led to increased MHC-I levels on tumor cells, and consequently enhanced the infiltration and functionality of CD8+ T cells, which bolstered antitumor immunity and improved the effectiveness of immune checkpoint blockade therapy. These findings have elucidated the intrinsic mechanisms of WNT7A-induced immune suppression, suggesting that therapeutic interventions targeting WNT7A hold promise for enhancing the efficacy of immunotherapy.
