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WNT11 Promotes immune evasion and resistance to Anti-PD-1 therapy in liver metastasis

Author

Listed:
  • Weiliang Jiang

    (No. 270 Dong’an Road
    No. 100 Haining Road
    No. 650 New Songjiang Road)

  • Bingjie Guan

    (No. 650 New Songjiang Road)

  • Hongcheng Sun

    (No. 650 New Songjiang Road)

  • Yushuai Mi

    (No. 247 Beiyuan Road)

  • Sanjun Cai

    (No. 270 Dong’an Road
    No. 270 Dong’an Road
    No. 270 Dong’an Road)

  • Rong Wan

    (No. 100 Haining Road
    No. 650 New Songjiang Road)

  • Xinxiang Li

    (No. 270 Dong’an Road
    No. 270 Dong’an Road)

  • Peng Lian

    (No. 270 Dong’an Road
    No. 270 Dong’an Road)

  • Dawei Li

    (No. 270 Dong’an Road
    No. 270 Dong’an Road)

  • Senlin Zhao

    (No. 270 Dong’an Road
    No. 270 Dong’an Road)

Abstract

Liver metastasis (LM) poses a significant challenge in cancer treatment, with limited available therapeutic options and poor prognosis. Understanding the dynamics of tumor microenvironment (TME) and immune interactions is crucial for developing effective treatments. We find that WNT11 promoted CD8+ T-cell exclusion and suppression, which was correlated with poor prognosis in LM. Mechanistically, WNT11-overexpressing tumor cells directly reduce CD8+ T-cell recruitment and activity by decreasing CXCL10 and CCL4 expression through CAMKII-mediated β-catenin/AFF3 downregulation. WNT11-overexpressing tumor cells promote immunosuppressive macrophage polarization by inducing IL17D expression via the CAMKII/NF-κB pathway, which result in CD8+ T-cell suppression. Moreover, CAMKII inhibition increases the efficacy of anti-PD-1 therapy in mouse model of LM. Serum expression of WNT11 is identified as a potential minimally invasive biomarker in the management of colorectal cancer-LM with immunotherapy. Our findings highlight WNT11/CAMKII axis as a critical regulator of the TME and a promising target for immunotherapy in patients with LM.

Suggested Citation

  • Weiliang Jiang & Bingjie Guan & Hongcheng Sun & Yushuai Mi & Sanjun Cai & Rong Wan & Xinxiang Li & Peng Lian & Dawei Li & Senlin Zhao, 2025. "WNT11 Promotes immune evasion and resistance to Anti-PD-1 therapy in liver metastasis," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56714-z
    DOI: 10.1038/s41467-025-56714-z
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    References listed on IDEAS

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    1. Hao Chen & Mai Chan Lau & Michael Thomas Wong & Evan W Newell & Michael Poidinger & Jinmiao Chen, 2016. "Cytofkit: A Bioconductor Package for an Integrated Mass Cytometry Data Analysis Pipeline," PLOS Computational Biology, Public Library of Science, vol. 12(9), pages 1-17, September.
    2. Petra Pandur & Matthias Läsche & Leonard M. Eisenberg & Michael Kühl, 2002. "Wnt-11 activation of a non-canonical Wnt signalling pathway is required for cardiogenesis," Nature, Nature, vol. 418(6898), pages 636-641, August.
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