WNT11 Promotes immune evasion and resistance to Anti-PD-1 therapy in liver metastasis
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 promo...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56714-z |
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| author | Weiliang Jiang Bingjie Guan Hongcheng Sun Yushuai Mi Sanjun Cai Rong Wan Xinxiang Li Peng Lian Dawei Li Senlin Zhao |
| author_facet | Weiliang Jiang Bingjie Guan Hongcheng Sun Yushuai Mi Sanjun Cai Rong Wan Xinxiang Li Peng Lian Dawei Li Senlin Zhao |
| author_sort | Weiliang Jiang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d76b68b2efe04878a54c195b138c0d73 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d76b68b2efe04878a54c195b138c0d732025-02-09T12:45:12ZengNature PortfolioNature Communications2041-17232025-02-0116111810.1038/s41467-025-56714-zWNT11 Promotes immune evasion and resistance to Anti-PD-1 therapy in liver metastasisWeiliang Jiang0Bingjie Guan1Hongcheng Sun2Yushuai Mi3Sanjun Cai4Rong Wan5Xinxiang Li6Peng Lian7Dawei Li8Senlin Zhao9Cancer Institute, Fudan University Shanghai Cancer Center, No. 270 Dong’an RoadDepartment of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 New Songjiang RoadDepartment of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 New Songjiang RoadDepartment of Gastrointestinal Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 247 Beiyuan RoadCancer Institute, Fudan University Shanghai Cancer Center, No. 270 Dong’an RoadDepartment of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining RoadDepartment of Colorectal Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’an RoadDepartment of Colorectal Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’an RoadDepartment of Colorectal Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’an RoadDepartment of Colorectal Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’an RoadAbstract 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.https://doi.org/10.1038/s41467-025-56714-z |
| spellingShingle | Weiliang Jiang Bingjie Guan Hongcheng Sun Yushuai Mi Sanjun Cai Rong Wan Xinxiang Li Peng Lian Dawei Li Senlin Zhao WNT11 Promotes immune evasion and resistance to Anti-PD-1 therapy in liver metastasis Nature Communications |
| title | WNT11 Promotes immune evasion and resistance to Anti-PD-1 therapy in liver metastasis |
| title_full | WNT11 Promotes immune evasion and resistance to Anti-PD-1 therapy in liver metastasis |
| title_fullStr | WNT11 Promotes immune evasion and resistance to Anti-PD-1 therapy in liver metastasis |
| title_full_unstemmed | WNT11 Promotes immune evasion and resistance to Anti-PD-1 therapy in liver metastasis |
| title_short | WNT11 Promotes immune evasion and resistance to Anti-PD-1 therapy in liver metastasis |
| title_sort | wnt11 promotes immune evasion and resistance to anti pd 1 therapy in liver metastasis |
| url | https://doi.org/10.1038/s41467-025-56714-z |
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