2. Academic Validation
  3. Targeting Dicer reprograms tumor-associated macrophages to promote anti-tumoral immunity in colorectal cancer liver metastasis

Targeting Dicer reprograms tumor-associated macrophages to promote anti-tumoral immunity in colorectal cancer liver metastasis

  • J Nanobiotechnology. 2025 Jun 6;23(1):421. doi: 10.1186/s12951-025-03518-4.
Shenglong Xia # 1 2 3,  Wenwen Chen # 1 2 3,  Zhengyang Xu # 1 2 3,  Yuzhen Gao 4,  Jingyu Chen 1 2 3,  Ning Ding 1 2 3,  Ying Zhang 1 2 3,  Tianhua Zhou 1 3 5 6,  Xuefei Zhou 7,  Xiangrui Liu 8 9 10 11 12,  Meng Xue 13 14 15
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
  • 2 Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 3 Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 4 Department of Clinical Laboratory, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China.
  • 5 Department of Cell Biology and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
  • 6 Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, Zhejiang, 310009, China.
  • 7 International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China. zhouxf@zju.edu.cn.
  • 8 Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China. xiangrui@zju.edu.cn.
  • 9 Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China. xiangrui@zju.edu.cn.
  • 10 Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, Zhejiang, 310009, China. xiangrui@zju.edu.cn.
  • 11 Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China. xiangrui@zju.edu.cn.
  • 12 Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, Zhejiang, 310027, China. xiangrui@zju.edu.cn.
  • 13 Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China. xuemeng@zju.edu.cn.
  • 14 Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, 310058, China. xuemeng@zju.edu.cn.
  • 15 Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China. xuemeng@zju.edu.cn.
  • # Contributed equally.
PMID: 40481520 DOI: 10.1186/s12951-025-03518-4
Abstract

Background: Tumor-associated macrophages (TAMs) contribute significantly to immunosuppression in colorectal Cancer liver metastasis (CRLM), leading to high aggressiveness and poor prognosis. However, the key molecules involved in shaping TAMs toward the pro-tumoral phenotype in CRLM remain unclear, limiting the development of macrophage-mediated immunotherapies for CRLM.

Results: In this study, we showed that DICER1 was highly expressed in TAMs and closely associated with M2 polarization in CRLM. Knockdown of Dicer, encoded by DICER1 in humans (or Dicer1 in mice), skewed macrophages toward an anti-tumoral M1 phenotype, with increased expression of pro-inflammatory cytokines and tumor cell phagocytosis, thereby suppressing tumor growth in mice. An M2 macrophage-targeting nanosystem was developed to deliver Dicer1 siRNA for selectively downregulating Dicer expression in M2 macrophages. In situ manipulation of TAMs with the nanoparticle exerted a significant anti-tumor effect with an improved immune microenvironment in a CRLM mouse model. Macrophage depletion experiments further suggested that this effect was largely dependent on the presence of TAMs. Mechanistically, Dicer inhibition reprogrammed M2-like macrophages through downregulation of miR-148a-3p and miR-1981-5p.

Conclusion: Our study uncovered the central role of Dicer in the M2 polarization of TAMs, in turn suggesting a promising therapeutic strategy for CRLM.

Keywords

Colorectal cancer; Dicer; Liver metastasis; RNA-lipid nanoparticles; Tumor-associated macrophages.

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