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 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.

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Supplementary data

Supplementary Table 1

The sequences of qPCR primers.

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Supplementary Table 2

Antibodies used for WB.

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Supplementary Table 3

2D interaction maps of small molecules obtained via protein screening of the ChemBridge library.

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Figure S1

Figure S1 High WNT7A expression correlates with low CTL cell infiltration, reduced MHC-I expression, and unfavorable patient survival.

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Figure S2

Figure S2 Blocking WNT7A leads to an increase in MHC-I expression.

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Figure S3

Figure S3 WNT7A blockage inhibits tumor growth and enhances anti-tumor immunity.

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Figure S4

Figure S4 Inhibition of WNT7A leads to the upregulation of MHC-I via the NF-κB pathway.

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Figure S5

Figure S5 Blocking WNT7A synergizes with ICB.

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Figure S6

Figure S6 Discovery of small chemical inhibitors targeting WNT7A–FZD5.

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Figure S7

Figure S7 1365-0109 improves ICB efficacy without significant toxic side effects.

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