Abstract
Liver resection is the primary curative treatment for early-stage hepatocellular carcinoma (HCC); however, high recurrence rates remain a major challenge in the absence of effective prognostic and preventive strategies. Here, we identified surgery-induced C-C motif chemokine ligand 11 (CCL11) as a pivotal driver of HCC recurrence through dual mechanisms of immunosuppression and tumor invasiveness. Elevated postoperative circulating CCL11 levels correlated strongly with HCC recurrence and poorer survival, and their integration with clinical parameters enhanced the predictive accuracy of HCC recurrence. Mechanistically, hepatic injury-induced CCL11 recruited immunosuppressive CCR5+CD206+ M2-like macrophages into the residual liver. These macrophages exhibited enhanced PD-L1 expression via activation of the CCL11/IKK/IκB/NF-κB1 axis and promoted regulatory T cell (Treg) induction from naïve CD4+ T cells. Concurrently, CCL11-CCR3 signaling in HCC cells activated PI3K/AKT/MafK to upregulate MMP13, enhancing the invasion ability of HCC cells. In orthotopic models, CCL11 enrichment increased tumor burden and extrahepatic metastases, while post-resection anti-CCL11 therapy reduced HCC recurrence and extended the survival rate of tumor-bearing mice. Our findings unveil CCL11 as a master regulator of the pro-tumorigenic niche post-resection, driving recurrence through coordinated immune evasion and promoting tumor invasiveness. Targeting the CCL11-CCR5/CCR3 axis presents a promising strategy to improve HCC surgical outcomes.
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Acknowledgements
The authors thank Surgical Tissue Bank and staff, Dr. Wan-Ching Yu and Miss Fion Sin for preparing the clinical samples, and Dr. Jana Yim Hung Wo and Dr. Hoi Chung Shiu for assisting the animal and cell experiments, respectively.
Funding
This work was supported by grants from the Shenzhen Science and Technology Program of Shenzhen Science and Technology Innovation Commission (JCYJ20240813113042055, JCYJ20210324114403010) and the Theme-based Research Scheme of the Research Grant Council of Hong Kong (TRS: T12-703/19 R).
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Study concept and design: J Wang, K Man, and K Ng; Acquisition of data: J Wang, O Yeung, and W Qiu; Analysis and interpretation of data: J Wang, O Yeung, L Pang, X Yang, T Ding, J Liu, and K Ng; Statistical analysis: J Wang, J Liu, T Cheung, Z Hu, and K Ng; Drafting of the manuscript: J Wang and K Ng; Critical revision of the manuscript for important intellectual content: J Wang, O Yeung, W Qiu, L Pang, J Liu, X Yang, S Zeng, T Ding, Z Wang, Z Hu, T Cheung, K Man, and K Ng; Administrative, technical, or material support: T Cheung, K Man and K Ng; Final approval of the version to be submitted: J Wang, O Yeung, W Qiu, L Pang, J Liu, X Yang, S Zeng, T Ding, Z Wang, Z Hu, T Cheung, K Man, and K Ng.
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Wang, J., Yeung, O.WH., Qiu, W. et al. CCL11 promotes hepatocellular carcinoma recurrence after surgery by potentiating immunosuppressive CCR5 + CD206 + M2-like macrophages and promoting tumor invasiveness. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08508-4
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DOI: https://doi.org/10.1038/s41419-026-08508-4
