2. Academic Validation
  3. WNT11 Promotes immune evasion and resistance to Anti-PD-1 therapy in liver metastasis

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

  • Nat Commun. 2025 Feb 7;16(1):1429. doi: 10.1038/s41467-025-56714-z.
Weiliang Jiang # 1 2 3,  Bingjie Guan # 4,  Hongcheng Sun # 4,  Yushuai Mi # 5,  Sanjun Cai 1 6 7,  Rong Wan 2 3,  Xinxiang Li 6 7,  Peng Lian 6 7,  Dawei Li 8 9,  Senlin Zhao 10 11
Affiliations

Affiliations

  • 1 Cancer Institute, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, China.
  • 2 Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining Road, Shanghai, China.
  • 3 Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, No. 650 New Songjiang Road, Shanghai, China.
  • 4 Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 New Songjiang Road, Shanghai, China.
  • 5 Department of Gastrointestinal Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 247 Beiyuan Road, Jinan, Shandong, China.
  • 6 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, China.
  • 7 Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong'an Road, Shanghai, China.
  • 8 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, China. li_dawei@fudan.edu.cn.
  • 9 Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong'an Road, Shanghai, China. li_dawei@fudan.edu.cn.
  • 10 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, China. sunshinezsl1989@163.com.
  • 11 Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong'an Road, Shanghai, China. sunshinezsl1989@163.com.
  • # Contributed equally.
PMID: 39920102 DOI: 10.1038/s41467-025-56714-z
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.

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