Research advances in the tumor microenvironment of colorectal cancer liver metastases_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WANG Ercong ¹ , JIANG Lei ² , CHEN Tao ¹ , YAN Junqian ¹ , CHEN Yang ¹ , LI Fang ¹ ,  WANG Jun ²

1. The First Clinical College of Medicine, Lanzhou University, Lanzhou 730000, P. R. China;
2. Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, P. R. China;

Corresponding?author：

WANG Jun, Email: juan_phd@163.com

Keywords：

colorectal cancer; colorectal cancer liver metastasis; tumor microenvironment; molecular targeted therapy

DOI：

10.7507/1007-9424.202506114

Video：

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Objective This study aims to systematically review the dynamic evolution mechanisms of the tumor microenvironment (TME) in colorectal cancer liver metastasis (CRLM), to provide a theoretical basis for developing early diagnostic biomarkers and novel therapeutic targets for CRLM. Methods By integrating existing research, this review focuses on the key multi-step processes involved in CRLM-TME formation. It elaborates on the complex interactions among tumor cells, stromal cells, immune components, and key signaling pathways during this process, with an emphasis on their multi-factorial interplay. Results The formation of the CRLM-TME involves several key steps: remote regulation by the primary tumor, specific recruitment of immune cells, adaptive remodeling of the liver microenvironment, and final colonization of the metastatic sites. This process is collectively driven by various factors such as tumor-derived metabolites, specific immune cell subsets, stromal components, and neovascularization, ultimately acts on the entire cascade of colorectal cancer cell invasion, migration, and colonization into the liver. Conclusions The CRLM-TME plays a critical role in the development, progression, treatment and drug resistance of CRLM. In-depth exploration of its mechanisms can provide direction for the development of early diagnostic biomarkers and therapies targeting the CRLM-TME, thereby aiming to improve the prognosis of CRLM patients.

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1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
2. 中國醫師協會外科醫師分會, 中華醫學會外科學分會胃腸外科學組, 中華醫學會外科學分會結直腸外科學組, 等. 中國結直腸癌肝轉移診斷和綜合治療指南(2023版). 中國實用外科雜志, 2023, 15(2): 86-99.
3. Benson AB, Venook AP, Adam M, et al. Colon Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw, 2024, 22(2 D): e240029. doi: 10.6004/jnccn.2024.0029.
4. Mielgo A, Schmid MC. Liver tropism in cancer: the hepatic metastatic niche. Cold Spring Harb Perspect Med, 2020, 10(3): a037259. doi: 10.1101/cshperspect.a037259.
5. Liu Y, Cao X. Characteristics and significance of the pre-metastatic niche. Cancer Cell, 2016, 30(5): 668-681.
6. Peinado H, Lavotshkin S, Lyden D. The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol, 2011, 21(2): 139-146.
7. Min BS, Kim NK, Jeong HC, et al. High levels of serum VEGF and TIMP-1 are correlated with colon cancer liver metastasis and intrahepatic recurrence after liver resection. Oncol Lett, 2012, 4(1): 123-130.
8. Kaplan RN, Riba RD, Zacharoulis S, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature, 2005, 438(7069): 820-827.
9. Jin Z, Li Y, Yi H, et al. Pathogenetic development, diagnosis and clinical therapeutic approaches for liver metastasis from colorectal cancer (Review). Int J Oncol, 2025, 66(3): 22. doi: 10.3892/ijo.2025.5728.
10. Calon A, Espinet E, Palomo-Ponce S, et al. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell, 2012, 22(5): 571-584.
11. Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell, 2010, 141(1): 52-67.
12. Liu Y, Zhang X, Gu W, et al. Unlocking the crucial role of cancer-associated fibroblasts in tumor metastasis: Mechanisms and therapeutic prospects. J Adv Res, 2025, 71: 399-413.
13. Watabe T, Takahashi K, Pietras K, et al. Roles of TGF-β signals in tumor microenvironment via regulation of the formation and plasticity of vascular system. Semin Cancer Biol, 2023, 92: 130-138.
14. Hoshino A, Costa-Silva B, Shen TL, et al. Tumour exosome integrins determine organotropic metastasis. Nature, 2015, 527(7578): 329-335.
15. Chen J, Cui L, Lu S, et al. Amino acid metabolism in tumor biology and therapy. Cell Death Dis, 2024, 15(1): 42. doi: 10.1038/s41419-024-06435-w.
16. Zhao S, Mi Y, Guan B, et al. Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer. J Hematol Oncol, 2020, 13(1): 156. doi: 10.1186/s13045-020-00991-2.
17. Pei W, Wei K, Wu Y, et al. Colorectal cancer tumor cell-derived exosomal miR-203a-3p promotes CRC metastasis by targeting PTEN-induced macrophage polarization. Gene, 2023, 885: 147692. doi: 10.1016/j.gene.2023.147692.
18. Gu Y, Mi Y, Cao Y, et al. The lncRNA MIR181A1HG in extracellular vesicles derived from highly metastatic colorectal cancer cells promotes liver metastasis by remodeling the extracellular matrix and recruiting myeloid-derived suppressor cells. Cell Biosci, 2025, 15(1): 23. doi: 10.1186/s13578-025-01365-2.
19. Zhang C, Tian C, Zhu R, et al. CircSATB1 promotes colorectal cancer liver metastasis through facilitating FKBP8 degradation via RNF25-Mediated ubiquitination. Adv Sci (Weinh), 2025, 12(13): e2406962. doi: 10.1002/advs.202406962.
20. Liu X, Liu J, Wang X, et al. Cancer-secreted exosomal miR-1246 promotes colorectal cancer liver metastasis by activating hepatic stellate cells. Mol Med, 2025, 31(1): 68. doi: 10.1186/s10020-025-01112-w.
21. Pathria P, Louis TL, Varner JA. Targeting tumor-associated macrophages in cancer. Trends Immunol, 2019, 40(4): 310-327.
22. Nicolini A, Ferrari P. Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy. Front Immunol, 2024, 15: 1353787. doi: 10.3389/fimmu.2024.1353787.
23. Petty AJ, Li A, Wang X, et al. Hedgehog signaling promotes tumor-associated macrophage polarization to suppress intratumoral CD8+ T cell recruitment. J Clin Invest, 2019, 129(12): 5151-5162.
24. Grossman JG, Nywening TM, Belt BA, et al. Recruitment of CCR2+ tumor associated macrophage to sites of liver metastasis confers a poor prognosis in human colorectal cancer. Oncoimmunology, 2018, 7(9): e1470729. doi: 10.1080/2162402X.2018.1470729.
25. Tu W, Gong J, Zhou Z, et al. TCF4 enhances hepatic metastasis of colorectal cancer by regulating tumor-associated macrophage via CCL2/CCR2 signaling. Cell Death Dis, 2021, 12(10): 882.
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29. Wang Y, Yang K, Li J, et al. Neutrophil extracellular traps in cancer: from mechanisms to treatments. Clin Transl Med, 2025, 15(6): e70368. doi: 10.1002/ctm2.70368.
30. Cao X, Lan Q, Xu H, et al. Granulocyte-like myeloid-derived suppressor cells: the culprits of neutrophil extracellular traps formation in the pre-metastatic niche. Int Immunopharmacol, 2024, 143(Pt 3): 113500. doi: 10.1016/j.intimp.2024.113500.
31. Zhang W, Ling J, Xu B, et al. Gut microbiome-mediated monocytes promote liver metastasis. Int Immunopharmacol, 2024, 133: 111877. doi: 10.1016/j.intimp.2024.111877.
32. Jiang X, Wang J, Deng X, et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer, 2019, 18(1): 10. doi: 10.1186/s12943-018-0928-4.
33. Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res, 2020, 10(3): 727-42.
34. Chen X, Du Z, Huang M, et al. Circulating PD-L1 is associated with T cell infiltration and predicts prognosis in patients with CRLM following hepatic resection. Cancer Immunol Immunother, 2022, 71(3): 661-674.
35. Tan HX, Gong WZ, Zhou K, et al. CXCR4/TGF-β1 mediated hepatic stellate cells differentiation into carcinoma-associated fibroblasts and promoted liver metastasis of colon cancer. Cancer Biol Ther, 2020, 21(3): 258-268.
36. Zhao S, Mi Y, Zheng B, et al. Highly-metastatic colorectal cancer cell released miR-181a-5p-rich extracellular vesicles promote liver metastasis by activating hepatic stellate cells and remodelling the tumour microenvironment. J Extracell Vesicles, 2022, 11(1): e12186. doi: 10.1002/jev2.12186.
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