Rewiring Immune Evasion in Liver Metastases: WNT11 as a Central Node — A Mini Review

Xiaoling Wang¹Youcai Huang²Tingting Luo³Qinxian Liu²Yu Tian³Xiaoyu Hu³Yi Zheng³Shumin Fang³Yanyang Tu^3*Haining Zhen^4*Guo Yu^5*

• ¹Science Research Center, Huizhou Central People's Hospital, Guangdong Medical University, Guangdong, China
• ²Huizhou Central People's Hospital, Guangdong Medical University, Guangdong, China
• ³Huizhou Central People's Hospital, Huizhou, China
• ⁴Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University,, Xi'an, China
• ⁵Zhuhai People's Hospital(The Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University), Zhuhai, China

Liver metastasis (LM) poses a formidable barrier to effective immunotherapy, largely due to its uniquely immunosuppressive microenvironment and resistance to immune checkpoint blockade (ICB).Among emerging mechanisms, WNT11, a non-canonical WNT ligand, has been identified as a preclinical modulator of immune evasion in LM. Acting through a calcium-dependent CAMKII signaling pathway axis, WNT11 suppresses CD8⁺ T-cell recruitment via downregulation of chemokines such as CXCL10 and CCL4 and promotes M2-like macrophage polarization through IL17D induction. This dual mechanism contributes to the formation of an immune-excluded, tolerogenic niche that undermines the efficacy of anti-PD-1 therapies. Targeting the WNT11/CAMKII axis restores immune infiltration and sensitizes LM to ICB in preclinical models, highlighting a promising therapeutic strategy. Although no direct WNT11-targeted therapies are currently available, multiple pharmacological strategies targeting its proximal and downstream effectors — such as FZD/ROR, CAMKII, PKC/JNK/NFAT, and associated crosstalk pathways like TGF-β, IDO1, and myeloid axes—are under active exploration. Additionally, circulating WNT11 levels may also serve as a predictive biomarker for patient stratification and treatment monitoring. Despite challenges related to pathway complexity and tumor heterogeneity, this mini review synthesizes recent advances in understanding the WNT11-driven tumor-immune axis and proposes a translational roadmap for combination strategies to overcome ICB resistance in liver metastasis..