Liver Metastasis in Cancer: Molecular Mechanisms and Management

Abstract

Liver metastasis is a leading cause of mortality from malignant tumors and significantly impairs the efficacy of therapeutic interventions. In recent years, both preclinical and clinical research have made significant progress in understanding the molecular mechanisms and therapeutic strategies of liver metastasis. Metastatic tumor cells from different primary sites undergo highly similar biological processes, ultimately achieving ectopic colonization and growth in the liver. In this review, we begin by introducing the inherent metastatic-friendly features of the liver. We then explore the panorama of liver metastasis and conclude the three continuous, yet distinct phases based on the liver’s response to metastasis. This includes metastatic sensing stage, metastatic stress stage, and metastasis support stage. We discuss the intricate interactions between metastatic tumor cells and various resident and recruited cells. In addition, we emphasize the critical role of spatial remodeling of immune cells in liver metastasis. Finally, we review the recent advancements and the challenges faced in the clinical management of liver metastasis. Future precise antimetastatic treatments should fully consider individual heterogeneity and implement different targeted interventions based on stages of liver metastasis.

Keywords

liver metastasis / spatial oncology / therapeutics / tumor microenvironment

References

[1] D. Hanahan, “Hallmarks of Cancer: New Dimensions,” Cancer Discovery 12, no. 1 (2022): 31–46.

[2] S. Wang, Y. Feng, J. Swinnen, R. Oyen, Y. Li, and Y. Ni, “Incidence and Prognosis of Liver Metastasis at Diagnosis: A Pan-Cancer Population-Based Study,” American Journal of Cancer Research 10, no. 5 (2020): 1477–1517.

[3] K. R. Hess, G. R. Varadhachary, S. H. Taylor, et al., “Metastatic Patterns in Adenocarcinoma,” Cancer 106, no. 7 (2006): 1624–1633.

[4] S. Milette, J. K. Sicklick, A. M. Lowy, P. Brodt, “Molecular Pathways: Targeting the Microenvironment of Liver Metastases,” Clinical Cancer Research 23, no. 21 (2017): 6390–6399.

[5] J. Massagué and K. Ganesh, “Metastasis-Initiating Cells and Ecosystems,” Cancer Discovery 11, no. 4 (2021): 971–994.

[6] J. Engstrand, H. Nilsson, C. Strömberg, et al., “Colorectal Cancer Liver Metastases—A Population-Based Study on Incidence, Management and Survival,” BMC cancer 18, no. 1 (2018): 78.

[7] Y. Meyer, A. Bohlok, D. Höppener, et al., “Histopathological Growth Patterns of Resected Non-colorectal, Non-Neuroendocrine Liver Metastases: A Retrospective Multicenter Study,” Clinical & Experimental Metastasis 39, no. 3 (2022): 433–442.

[8] Y. Gao, S. Chen, H. Wang, et al., “Liver Metastases Across Cancer Types Sharing Tumor Environment Immunotolerance Can Impede Immune Response Therapy and Immune Monitoring,” Journal of Advanced Research 61 (2024): 151–164.

[9] S. Paget, “The Distribution of Secondary Growths in Cancer of the Breast,” Cancer and Metastasis Reviews 8, no. 2 (1889): 98–101.

[10] E. F. Scanlon, “James Ewing Lecture. The Process of Metastasis,” Cancer 55, no. 6 (1985): 1163–1166.

[11] I. R. Hart and I. J. Fidler, “Role of Organ Selectivity in the Determination of Metastatic Patterns of B16 Melanoma,” Cancer Research 40, no. 7 (1980): 2281–2287.

[12] D. Tarin, J. E. Price, M. G. Kettlewell, et al., “Mechanisms of human Tumor Metastasis Studied in Patients With Peritoneovenous Shunts,” Cancer Research 44, no. 8 (1984): 3584–3592.

[13] G. Wang, J. Li, L. Bojmar, et al., “Tumour Extracellular Vesicles and Particles Induce Liver Metabolic Dysfunction,” Nature 618, no. 7964 (2023): 374–382.

[14] T. Qiao, W. Yang, X. He, et al., “Dynamic Differentiation of F4/80+ Tumor-Associated Macrophage and Its Role in Tumor Vascularization in a Syngeneic Mouse Model of Colorectal Liver Metastasis,” Cell Death & Disease 14, no. 2 (2023): 117.

[15] B. Ma, A. Wells, and A. M. Clark, “The Pan-therapeutic Resistance of Disseminated Tumor Cells: Role of Phenotypic Plasticity and the Metastatic Microenvironment,” Seminars in Cancer Biology 60 (2020): 138–147.

[16] X. J. Chen, A. Ren, L. Zheng, et al., “Pan-Cancer Analysis Identifies Liver Metastases as Negative Predictive Factor for Immune Checkpoint Inhibitors Treatment Outcome,” Frontiers in Immunology 12 (2021): 651086.

[17] J. Yu, M. D. Green, S. Li, et al., “Liver Metastasis Restrains Immunotherapy Efficacy via Macrophage-mediated T Cell Elimination,” Nature Medicine 27, no. 1 (2021): 152–164.

[18] Ö. Akgül, E. Çetinkaya, Ş. Ersöz, et al., “Role of Surgery in Colorectal Cancer Liver Metastases,” World Journal of Gastroenterology 20, no. 20 (2014): 6113–6122.

[19] S. Miwa, S. Miyagawa, A. Kobayashi, et al., “Predictive Factors for Intrahepatic Cholangiocarcinoma Recurrence in the Liver Following Surgery,” Journal of Gastroenterology 41, no. 9 (2006): 893–900.

[20] A. M. Clark, B. Ma, D. L. Taylor, et al., “Liver Metastases: Microenvironments and Ex-Vivo Models,” Experimental Biology and Medicine (Maywood, N.J.) 241, no. 15 (2016): 1639–1652.

[21] O. Ohtani and Y. Ohtani, “Lymph Circulation in the Liver,” Anatomical record (Hoboken, N.J.) 291, no. 6 (2008): 643–652.

[22] K. Kumagai, K. Shimizu, N. Yokoyama, et al., “Gastrointestinal Cancer Metastasis and Lymphatic Advancement,” Surgery Today 40, no. 4 (2010): 301–306.

[23] D. D. Shi, J. A. Guo, H. I. Hoffman, et al., “Therapeutic Avenues for Cancer Neuroscience: Translational Frontiers and Clinical Opportunities,” Lancet Oncology 23, no. 2 (2022): e62–e74.

[24] W. Xu, J. Liu, J. Zhang, et al., “Tumor Microenvironment Crosstalk Between Tumors and the Nervous System in Pancreatic Cancer: Molecular Mechanisms and Clinical Perspectives,” Biochimica et Biophysica Acta: Reviews on Cancer 1879, no. 1 (2024): 189032.

[25] P. Altea-Manzano, G. Doglioni, Y. Liu, et al., “A Palmitate-rich Metastatic Niche Enables Metastasis Growth via p65 Acetylation Resulting in Pro-metastatic NF-κB Signaling,” Nature Cancer 4, no. 3 (2023): 344–364.

[26] X. Li, P. Ramadori, D. Pfister, et al., “The Immunological and Metabolic Landscape in Primary and Metastatic Liver Cancer,” Nature Reviews Cancer 21, no. 9 (2021): 541–557.

[27] N. Aizarani, A. Saviano, et al., “A Human Liver Cell Atlas Reveals Heterogeneity and Epithelial Progenitors,” Nature 572, no. 7768 (2019): 199–204.

[28] N. Berndt, E. Kolbe, R. Gajowski, et al., “Functional Consequences of Metabolic Zonation in Murine Livers: Insights for an Old Story,” Hepatology 73, no. 2 (2021): 795–810.

[29] K. B. Halpern, R. Shenhav, O. Matcovitch-Natan, et al., “Single-cell Spatial Reconstruction Reveals Global Division of Labour in the Mammalian Liver,” Nature 542, no. 7641 (2017): 352–356.

[30] B. Faubert, A. Solmonson, and R. J. DeBerardinis, “Metabolic Reprogramming and Cancer Progression,” Science 368, no. 6487 (2020).

[31] L. Xia, L. Oyang, J. Lin, et al., “The Cancer Metabolic Reprogramming and Immune Response,” Molecular Cancer 20, no. 1 (2021): 28.

[32] T. Schild, V. Low, J. Blenis, et al., “Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization,” Cancer Cell 33, no. 3 (2018): 347–354.

[33] R. Li, X. Liu, X. Huang, et al., “Single-cell Transcriptomic Analysis Deciphers Heterogenous Cancer Stem-Like Cells in Colorectal Cancer and Their Organ-specific Metastasis,” Gut 73, no. 3 (2024): 470–484.

[34] A. M. Khaliq, M. Rajamohan, O. Saeed, et al., “Spatial Transcriptomic Analysis of Primary and Metastatic Pancreatic Cancers Highlights Tumor Microenvironmental Heterogeneity,” Nature Genetics 56, no. 11 (2024): 2455–2465.

[35] F. Dupuy, S. Tabariès, S. Andrzejewski, et al., “PDK1-Dependent Metabolic Reprogramming Dictates Metastatic Potential in Breast Cancer,” Cell metabolism 22, no. 4 (2015): 577–589.

[36] J. M. Loo, A. Scherl, A. Nguyen, et al., “Extracellular Metabolic Energetics Can Promote Cancer Progression,” Cell 160, no. 3 (2015): 393–406.

[37] K. Taniguchi, K. Sugihara, T. Miura, et al., “Cholesterol Synthesis Is Essential for the Growth of Liver Metastasis-prone Colorectal Cancer Cells,” Cancer Science 115, no. 11 (2024): 3817–3828.

[38] S. Sivanand, Y. Gultekin, P. S. Winter, et al., “Cancer Tissue of Origin Constrains the Growth and Metabolism of Metastases,” Nature Metabolism 6, no. 9 (2024): 1668–1681.

[39] O. Goldman, L. N. Adler, E. Hajaj, et al., “Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis,” Cancer discovery 13, no. 7 (2023): 1616–1635.

[40] M. Yang and C. Zhang, “The Role of Liver Sinusoidal Endothelial Cells in Cancer Liver Metastasis,” American Journal of Cancer Research 11, no. 5 (2021): 1845–1860.

[41] K. K. Bence and M. J. Birnbaum, “Metabolic Drivers of Non-alcoholic Fatty Liver Disease,” Molecular Metabolism 50 (2021): 101143.

[42] Z. Wang, S. Y. Kim, W. Tu, et al., “Extracellular Vesicles in Fatty Liver Promote a Metastatic Tumor Microenvironment,” Cell metabolism 35, no. 7 (2023): 1213.

[43] C. N. Jenne and P. Kubes, “Immune Surveillance by the Liver,” Nature Immunology 14, no. 10 (2013): 996–1006.

[44] J. Zhao, S. Zhang, Y. Liu, et al., “Single-cell RNA Sequencing Reveals the Heterogeneity of Liver-resident Immune Cells in human,” Cell Discovery 6 (2020): 22.

[45] W. Y. Lee, T. J. Moriarty, C. H. Wong, et al., “An Intravascular Immune Response to Borrelia burgdorferi Involves Kupffer Cells and iNKT Cells,” Nature Immunology 11, no. 4 (2010): 295–302.

[46] Q. You, L. Cheng, R. M. Kedl, et al., “Mechanism of T Cell Tolerance Induction by Murine Hepatic Kupffer Cells,” Hepatology 48, no. 3 (2008): 978–990.

[47] J. Shi, G. E. Gilbert, Y. Kokubo, et al., “Role of the Liver in Regulating Numbers of Circulating Neutrophils,” Blood 98, no. 4 (2001): 1226–1230.

[48] F. Heymann, J. Peusquens, I. Ludwig-Portugall, et al., “Liver Inflammation Abrogates Immunological Tolerance Induced by Kupffer Cells,” Hepatology 62, no. 1 (2015): 279–291.

[49] J. Shi, H. Fujieda, Y. Kokubo, et al., “Apoptosis of Neutrophils and Their Elimination by Kupffer Cells in Rat Liver,” Hepatology 24, no. 5 (1996): 1256–1263.

[50] V. Racanelli and B. Rehermann, “The Liver as an Immunological Organ,” Hepatology 43, (2 Suppl 1) (2006): S54–S62.

[51] J. Wu, Z. Meng, M. Jiang, et al., “Toll-Like Receptor-induced Innate Immune Responses in Non-parenchymal Liver Cells Are Cell Type-specific,” Immunology 129, no. 3 (2010): 363–374.

[52] P. A. Knolle and A. Limmer, “Control of Immune Responses by Savenger Liver Endothelial Cells,” Swiss Medical Weekly: Official Journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology 133, no. 37–38 (2003): 501–506.

[53] F. A. Schildberg, S. I. Hegenbarth, B. Schumak, et al., “Liver Sinusoidal Endothelial Cells Veto CD8 T Cell Activation by Antigen-presenting Dendritic Cells,”. European Journal of Immunology 38, no. 4 (2008): 957–967.

[54] A. Schurich, M. Berg, D. Stabenow, et al., “Dynamic Regulation of CD8 T Cell Tolerance Induction by Liver Sinusoidal Endothelial Cells,” Journal of Immunology 184, no. 8 (2010): 4107–4114.

[55] M. Dudek, K. Lohr, S. Donakonda, et al., “IL-6-induced FOXO1 Activity Determines the Dynamics of Metabolism in CD8 T Cells Cross-primed by Liver Sinusoidal Endothelial Cells,” Cell Reports 38, no. 7 (2022): 110389.

[56] M. Berg, G. Wingender, D. Djandji, et al., “Cross-presentation of Antigens From Apoptotic Tumor Cells by Liver Sinusoidal Endothelial Cells Leads to Tumor-specific CD8+ T Cell Tolerance,” European Journal of Immunology 36 no. 11 (2006): 2960–2970.

[57] L. Diehl, A. Schurich, R. Grochtmann, et al., “Tolerogenic Maturation of Liver Sinusoidal Endothelial Cells Promotes B7-homolog 1-dependent CD8+ T Cell Tolerance,” Hepatology 47 no. 1 (2008): 296–305.

[58] P. A. Knolle, T. Germann, U. Treichel, et al., “Endotoxin Down-regulates T Cell Activation by Antigen-presenting Liver Sinusoidal Endothelial Cells,” Journal of Immunology 162, no. 3 (1999): 1401–1407.

[59] P. A. Knolle, A. Uhrig, S. Hegenbarth, et al., “IL-10 Down-regulates T Cell Activation by Antigen-presenting Liver Sinusoidal Endothelial Cells Through Decreased Antigen Uptake via the Mannose Receptor and Lowered Surface Expression of Accessory Molecules,” Clinical and Experimental Immunology 1998; 114(3): 427–433.

[60] X. Zhang, Z. Meng, S. Qiu, et al., “Lipopolysaccharide-induced Innate Immune Responses in Primary Hepatocytes Downregulates Woodchuck hepatitis Virus Replication via Interferon-independent Pathways,” Cellular Microbiology 11, no. 11 (2009): 1624–1637.

[61] J. Hou, J. Zhang, P. Cui, et al., “TREM2 sustains Macrophage-hepatocyte Metabolic Coordination in Nonalcoholic Fatty Liver Disease and Sepsis,” Journal of Clinical Investigation 131, no. 4 (2021): e135197.

[62] S. P. Davies, G. M. Reynolds, A. L. Wilkinson, et al., “Hepatocytes Delete Regulatory T Cells by Enclysis, a CD4(+) T Cell Engulfment Process,” Cell Reports 29, no. 6 (2019): 1610–1620.

[63] C. Wahl, P. Bochtler, L. Chen, et al., “B7-H1 on Hepatocytes Facilitates Priming of Specific CD8 T Cells but Limits the Specific Recall of Primed Responses,” Gastroenterology 135, no. 3 (2008): 980–988.

[64] A. Warren, D. G. Le Couteur, R. Fraser, et al., “T Lymphocytes Interact With Hepatocytes Through Fenestrations in Murine Liver Sinusoidal Endothelial Cells,” Hepatology 44, no. 5 (2006): 1182–1190.

[65] S. Burghardt, B. Claass, A. Erhardt, et al., “Hepatocytes Induce Foxp3⁺ Regulatory T Cells by Notch Signaling,” Journal of Leukocyte Biology 96, no. 4 (2014): 571–577.

[66] M. G. Lassen, J. R. Lukens, J. S. Dolina, et al., “Intrahepatic IL-10 Maintains NKG2A+Ly49-liver NK Cells in a Functionally Hyporesponsive state,” Journal of Immunology 184, no. 5 (2010): 2693–2701.

[67] P. A. Knolle and R. Thimme, “Hepatic Immune Regulation and Its Involvement in Viral hepatitis Infection,” Gastroenterology 146, no. 5 (2014): 1193–1207.

[68] B. Hoechst, T. Voigtlaender, L. Ormandy, et al., “Myeloid Derived Suppressor Cells Inhibit Natural Killer Cells in Patients With Hepatocellular Carcinoma via the NKp30 Receptor,” Hepatology 50, no. 3 (2009): 799–807.

[69] L. X. Zhou, Y. Z. Jiang, X. Q. Li, et al., “Myeloid-derived Suppressor Cells-induced Exhaustion of CD8 + T-cell Participates in Rejection After Liver Transplantation,” Cell Death & Disease 15, no. 7 (2024): 507.

[70] J. Nan, Y. F. Xing, B. Hu, et al., “Endoplasmic Reticulum Stress Induced LOX-1(+ ) CD15(+) Polymorphonuclear Myeloid-derived Suppressor Cells in Hepatocellular Carcinoma,” Immunology 154, no. 1 (2018): 144–155.

[71] P. Penaloza-MacMaster, A. O. Kamphorst, A. Wieland, et al., “Interplay Between Regulatory T Cells and PD-1 in Modulating T Cell Exhaustion and Viral Control During Chronic LCMV Infection,” Journal of Experimental Medicine 211, no. 9 (2014): 1905–1918.

[72] Z. Tian, X. Cao, Y. Chen, et al., “Regional Immunity in Tissue Homeostasis and Diseases,” Science China Life Sciences 59, no. 12 (2016): 1205–1209.

[73] C. Swanton, E. Bernard, C. Abbosh, et al., “Embracing Cancer Complexity: Hallmarks of Systemic Disease,” Cell 187, no. 7 (2024): 1589–1616.

[74] X. Wang, P. J. A. Eichhorn, and J. P Thiery, “TGF-β EMT, and Resistance to Anti-cancer Treatment,” Seminars in Cancer Biology 97 (2023): 1–11.

[75] G. Mucciolo, J. A. Henríquez and M. Jihad, et al., “EGFR-activated Myofibroblasts Promote Metastasis of Pancreatic Cancer,” Cancer Cell 42, no. 1 (2024): 101-118.

[76] D. V. F Tauriello, S. Palomo-Ponce, D. Stork, et al., “TGFβ Drives Immune Evasion in Genetically Reconstituted Colon Cancer Metastasis,” Nature 554, no. 7693 (2018): 538–543.

[77] L. Zhang, J. Xu, S. Zhou, et al., “Endothelial DGKG Promotes Tumor Angiogenesis and Immune Evasion in Hepatocellular Carcinoma,” Journal of Hepatology 80, no. 1 (2024): 82–98.

[78] K. Slattery, E. Woods, V. Zaiatz-Bittencourt, et al., “TGFβ Drives NK Cell Metabolic Dysfunction in human Metastatic Breast Cancer,” Journal for ImmunoTherapy of Cancer 9, no. 2 (2021): e002044.

[79] F. Zhang, Y. Yan, X. Cao, et al., “TGF-β-driven LIF Expression Influences Neutrophil Extracellular Traps (NETs) and Contributes to Peritoneal Metastasis in Gastric Cancer,” Cell Death & Disease 15, no. 3 (2024): 218.

[80] D. Liu, L. Li, X. X. Zhang, et al., “SIX1 Promotes Tumor Lymphangiogenesis by Coordinating TGFβ Signals That Increase Expression of VEGF-C,” Cancer Research 74, no. 19 (2014): 5597–5607.

[81] K. H. Pak, K. C. Park, and J. H Cheong., “VEGF-C Induced by TGF-β1 Signaling in Gastric Cancer Enhances Tumor-Induced Lymphangiogenesis,” BMC Cancer 19, no. 1 (2019): 799.

[82] Z. Zhao, D. Hao, L. Wang, et al., “CtBP Promotes Metastasis of Breast Cancer Through Repressing Cholesterol and Activating TGF-β Signaling,” Oncogene 2019; 38(12): 2076–2091.

[83] S. Yang, Y. Liu, M. Y. Li, et al., “FOXP3 Promotes Tumor Growth and Metastasis by Activating Wnt/β-Catenin Signaling Pathway and EMT in Non-small Cell Lung Cancer,” Molecular cancer 16, no. 1 (2017): 124.

[84] H. J. Li, F. Y. Ke, C. C. Lin, et al., “ENO1 Promotes Lung Cancer Metastasis via HGFR and WNT Signaling-Driven Epithelial-to-Mesenchymal Transition,” Cancer Research 81, no. 15 (2021): 4094–4109.

[85] V. Luga, L. Zhang, A. M Viloria-Petit, et al., “Exosomes Mediate Stromal Mobilization of Autocrine Wnt-PCP Signaling in Breast Cancer Cell Migration,” Cell 151, no. 7 (2012): 1542–1556.

[86] J. I. Park, A. S. Venteicher, J. Y. Hong, et al., “Telomerase Modulates Wnt Signalling by Association With Target Gene Chromatin,” Nature 460, no. 7251 (2009): 66–72.

[87] S. Malladi, D. G. Macalinao, and X. Jin, et al., “Metastatic Latency and Immune Evasion Through Autocrine Inhibition of WNT,” Cell 165, no. 1 (2016): 45–60.

[88] M. D. Wellenstein, S. B. Coffelt, D. E. M. Duits, et al., “Loss of p53 Triggers WNT-Dependent Systemic Inflammation to Drive Breast Cancer Metastasis,” Nature 572, no. 7770 (2019): 538–542.

[89] X. Huang, H. Zhu, Z. Gao, et al., “Wnt7a activates Canonical Wnt Signaling, Promotes Bladder Cancer Cell Invasion, and Is Suppressed by miR-370-3p,” Journal of Biological Chemistry 293, no. 18 (2018): 6693–6706.

[90] L. Wu, J. Xiao, D. Yi, et al., “Cytosolic Cadherin 4 Promotes Angiogenesis and Metastasis in Papillary Thyroid Cancer by Suppressing the Ubiquitination/Degradation of β-catenin,” Journal of Translational Medicine 22, no. 1 (2024): 201.

[91] Z. Xiao, X. Feng, Y. Zhou, et al., “Exosomal miR-10527-5p Inhibits Migration, Invasion, Lymphangiogenesis and Lymphatic Metastasis by Affecting Wnt/β-Catenin Signaling via Rab10 in Esophageal Squamous Cell Carcinoma,” International Journal of Nanomedicine 18 (2023): 95–114.

[92] L. Yan, M. Wu, T. Wang, et al., “Breast Cancer Stem Cells Secrete MIF to Mediate Tumor Metabolic Reprogramming That Drives Immune Evasion,” Cancer Research 84, no. 8 (2024): 1270–1285.

[93] J. Su, S. M. Morgani, C. J. David, et al., “TGF-β Orchestrates Fibrogenic and Developmental EMTs via the RAS Effector RREB1,” Nature 577. no. 7791 (2020): 566–571.

[94] S. Wen, Y. Hou, L. Fu, et al., “Cancer-associated Fibroblast (CAF)-derived IL32 Promotes Breast Cancer Cell Invasion and Metastasis via Integrin β3-p38 MAPK Signalling,” Cancer Letters 442 (2019): 320–332.

[95] H. Ma, G. Qi, F. Han, et al., “HMGB3 promotes the Malignant Phenotypes and Stemness of Epithelial Ovarian Cancer Through the MAPK/ERK Signaling Pathway,” Cell Communication and Signaling 21, no. 1 (2023): 144.

[96] L. Haas, A. Elewaut, C. L. Gerard, et al., “Acquired Resistance to Anti-MAPK Targeted Therapy Confers an Immune-evasive Tumor Microenvironment and Cross-resistance to Immunotherapy in Melanoma,” Nature Cancer 2, no. 7 (2021): 693–708.

[97] M. Wang, Y. Zhao, Z. Y. Yu, et al., “Glioma Exosomal microRNA-148a-3p Promotes Tumor Angiogenesis Through Activating the EGFR/MAPK Signaling Pathway via Inhibiting ERRFI1,” Cancer Cell International 20 (2020): 518.

[98] M. Dufies, S. Giuliano, D. Ambrosetti, et al., “Sunitinib Stimulates Expression of VEGFC by Tumor Cells and Promotes Lymphangiogenesis in Clear Cell Renal Cell Carcinomas,” Cancer Research 77, no. 5 (2017): 1212–1226.

[99] F. Li, C. He, H. Yao, et al., “Glutamate From Nerve Cells Promotes Perineural Invasion in Pancreatic Cancer by Regulating Tumor Glycolysis Through HK2 mRNA-m6A Modification,” Pharmacological Research 187 (2023): 106555.

[100] S. Liang, H. Guo, K. Ma, et al., “A PLCB1-PI3K-AKT Signaling Axis Activates EMT to Promote Cholangiocarcinoma Progression,” Cancer Research 81, no. 23 (2021): 5889–5903.

[101] B. Liu, X. Fang, D. L. Kwong, et al., “Targeting TROY-mediated P85a/AKT/TBX3 Signaling Attenuates Tumor Stemness and Elevates Treatment Response in Hepatocellular Carcinoma,” Journal of Experimental & Clinical Cancer Research 41, no. 1 (2022): 182.

[102] X. Wang, S. Zhang, and D. Jin, et al., “µ-opioid Receptor Agonist Facilitates Circulating Tumor Cell Formation in Bladder Cancer via the MOR/AKT/Slug Pathway: A Comprehensive Study Including Randomized Controlled Trial,” Cancer communications (London, England) 43, no. 3 (2023): 365–386.

[103] Z. Wang, X. Wang, Y. Xu, et al., “Mutations of PI3K-AKT-mTOR Pathway as Predictors for Immune Cell Infiltration and Immunotherapy Efficacy in dMMR/MSI-H Gastric Adenocarcinoma,” BMC Medicine [Electronic Resource] 20, no. 1 (2022): 133.

[104] N. Niu, X. Shen, L. Zhang, et al., “Tumor Cell-Intrinsic SETD2 Deficiency Reprograms Neutrophils to Foster Immune Escape in Pancreatic Tumorigenesis,” Advanced science (Weinheim, Baden-Württemberg, Germany) 10, no. 2 (2023): e2202937.

[105] D. Mao, Z. Zhou, H. Chen, et al., “Pleckstrin-2 Promotes Tumour Immune Escape From NK Cells by Activating the MT1-MMP-MICA Signalling Axis in Gastric Cancer,” Cancer Letters 572 (2023): 216351.

[106] D. Wang, X. Liu, W. Hong, et al., “Muscone Abrogates Breast Cancer Progression Through Tumor Angiogenic Suppression via VEGF/PI3K/Akt/MAPK Signaling Pathways,” Cancer Cell International 24, no. 1 (2024): 214.

[107] X. Li, Z. Wei, H. Yu, et al., “Secretory Autophagy-induced Bladder Tumour-derived Extracellular Vesicle Secretion Promotes Angiogenesis by Activating the TPX2-mediated Phosphorylation of the AURKA-PI3K-AKT Axis,” Cancer Letters 523 (2021): 10–28.

[108] X. Mei, J. Xiong, J. Liu, et al., “DHCR7 promotes Lymph Node Metastasis in Cervical Cancer Through Cholesterol Reprogramming-mediated Activation of the KANK4/PI3K/AKT Axis and VEGF-C Secretion,” Cancer Letters 584 (2024): 216609.

[109] J. Wang, Q. Li, F. Liang, et al., “Dickkopf-1 Drives Perineural Invasion via PI3K-AKT Signaling Pathway in Head and Neck Squamous Cancer,” Medical Communications 5, no, 4 (2020): e518.

[110] G. Hoxhaj and B. D Manning, “The PI3K-AKT Network at the Interface of Oncogenic Signalling and Cancer Metabolism,” Nature Reviews Cancer 20, no. 2 (2020): 74–88.

[111] L. E. Stevens, G. Peluffo, X. Qiu, et al., “JAK-STAT Signaling in Inflammatory Breast Cancer Enables Chemotherapy-Resistant Cell States,” Cancer Research 83, no. 2 (2023): 264–284.

[112] M. Shen, Z. Xu, W. Xu, et al., “Inhibition of ATM Reverses EMT and Decreases Metastatic Potential of Cisplatin-resistant Lung Cancer Cells Through JAK/STAT3/PD-L1 Pathway,” Journal of Experimental & Clinical Cancer Research 38, no. 1 (2019): 149.

[113] U. G. Lo, Y. A. Chen, J. Cen, et al., “The Driver Role of JAK-STAT Signalling in Cancer Stemness Capabilities Leading to New Therapeutic Strategies for Therapy-and Castration-resistant Prostate Cancer,” Clinical and translational medicine 2022; 12(8):e978.

[114] B. Chen, J. Hu, X. Hu, et al., “DENR Controls JAK2 Translation to Induce PD-L1 Expression for Tumor Immune Evasion,” Nature Communications 13, no. 1 (2022): 2059.

[115] C. K. Baumgartner, H. Ebrahimi-Nik, A. Iracheta-Vellve, et al., “The PTPN2/PTPN1 Inhibitor ABBV-CLS-484 Unleashes Potent Anti-tumour Immunity,” Nature 622, no. 7984 (2023): 850–862.

[116] R. R. Malla, S. Gopinath, C. S. Gondi, et al., “Cathepsin B and uPAR Knockdown Inhibits Tumor-induced Angiogenesis by Modulating VEGF Expression in Glioma,” Cancer Gene Therapy 18, no. 6 (2011): 419–434.

[117] J. Nigri, M. Gironella, C. Bressy, et al., “PAP/REG3A Favors Perineural Invasion in Pancreatic Adenocarcinoma and Serves as a Prognostic Marker,” Cellular and Molecular Life Sciences 74, no. 22 (2017): 4231–4243.

[118] T. M. Chang, Y. C. Chiang, C. W. Lee, et al., “CXCL14 Promotes Metastasis of Non-small Cell Lung Cancer Through ACKR2-depended Signaling Pathway,” International Journal of Biological Sciences 19, no. 5 (2023): 1455–1470.

[119] C. Ren, X. Han, C. Lu, et al., “Ubiquitination of NF-κB p65 by FBXW2 Suppresses Breast Cancer Stemness, Tumorigenesis, and Paclitaxel Resistance,” Cell Death and Differentiation 29, no. 2 (2022): 381–392.

[120] F. Antonangeli, A. Natalini, M. C. Garassino, et al., “Regulation of PD-L1 Expression by NF-κB in Cancer,” Frontiers in Immunology 11 (2020): 584626.

[121] M. Zhang, Z. Z. Liu, K. Aoshima, et al., “CECR2 drives Breast Cancer Metastasis by Promoting NF-κB Signaling and Macrophage-mediated Immune Suppression,” Science Translational Medicine 14, no. 630 (2022): eabf5473.

[122] R. Wang, Y. Ma, S. Zhan, et al., “B7-H3 promotes Colorectal Cancer Angiogenesis Through Activating the NF-κB Pathway to Induce VEGFA Expression,” Cell Death & Disease 11, no. 1 (2020): 55.

[123] C. Zhang, Y. Liao, P. Liu, et al., “FABP5 promotes Lymph Node Metastasis in Cervical Cancer by Reprogramming Fatty Acid Metabolism,” Theranostics 10, no. 15 (2020): 6561–6580.

[124] X. Wang, R. Liu, X. Qu, et al., “α-Ketoglutarate-Activated NF-κB Signaling Promotes Compensatory Glucose Uptake and Brain Tumor Development,” Molecular Cell 76, no. 1 (2019): 148–162.

[125] L. Chen, X. Lin, Y. Lei, et al., “Aerobic Glycolysis Enhances HBx-initiated Hepatocellular Carcinogenesis via NF-κBp65/HK2 Signalling,” Journal of Experimental & Clinical Cancer Research 41, no. 1 (2022): 329.

[126] B. Nguyen, C. Fong, A. Luthra, et al., “Genomic Characterization of Metastatic Patterns From Prospective Clinical Sequencing of 25, 000 Patients,” Cell 185, no. 3 (2022): 563–575.

[127] S. F. Bakhoum, B. Ngo, A. M. Laughney, et al., “Chromosomal Instability Drives Metastasis Through a Cytosolic DNA Response,” Nature 553, no. 7689 (2018): 467–472.

[128] J. Y. Lee, K. Park, E. Lee, et al., “Gene Expression Profiling of Breast Cancer Brain Metastasis,” Scientific Reports 6 (2016): 28623.

[129] S. Zhang, W. Fang, S. Zhou, et al., “Single Cell Transcriptomic Analyses Implicate an Immunosuppressive Tumor Microenvironment in Pancreatic Cancer Liver Metastasis,” Nature Communications 14, no. 1 (2023): 5123.

[130] J. Yang, P. Lin, M. Yang, et al., “Integrated Genomic and Transcriptomic Analysis Reveals Unique Characteristics of Hepatic Metastases and Pro-metastatic Role of Complement C1q in Pancreatic Ductal Adenocarcinoma,” Genome Biology 22, no. 1 (2021): 4.

[131] D. Fumagalli, T. R. Wilson, R. Salgado, et al., “Somatic Mutation, Copy Number and Transcriptomic Profiles of Primary and Matched Metastatic Estrogen Receptor-positive Breast Cancers,” Annals of Oncology 27, no. 10 (2016): 1860–1866.

[132] R. A. Moffitt, R. Marayati, E. L. Flate, et al., “Virtual Microdissection Identifies Distinct Tumor-and Stroma-specific Subtypes of Pancreatic Ductal Adenocarcinoma,” Nature Genetics 47, no. 10 (2015): 1168–1178.

[133] I. Albanese, A. G. Scibetta, M. Migliavacca, et al., “Heterogeneity Within and Between Primary Colorectal Carcinomas and Matched Metastases as Revealed by Analysis of Ki-ras and p53 Mutations,” Biochemical and Biophysical Research Communications 325, no. 3 (2004): 784–791.

[134] W. Mei, S. F. Tabrizi C. Godina, et al., “A Commonly Inherited Human PCSK9 Germline Variant Drives Breast Cancer Metastasis Via LRP1 Receptor,” Cell (2024).

[135] S. Gerstberger, Q. Jiang, K. Ganesh, “Metastasis,” Cell 186, no. 8 (2023): 1564–1579.

[136] F. de Sousa e Melo, A. V. Kurtova, J. M. Harnoss, et al., “A Distinct Role for Lgr5(+) Stem Cells in Primary and Metastatic Colon Cancer,” Nature 543, no. 7647 (2017): 676–680.

[137] A. Fumagalli, K. C. Oost, L. Kester, et al., “Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer,” Cell Stem Cell 26, no. 4 (2020): 569-578.

[138] K. Ganesh, H. Basnet, Y. Kaygusuz, et al., “L1CAM defines the Regenerative Origin of Metastasis-initiating Cells in Colorectal Cancer,” Nature Cancer 1, no. 1 (2020): 28–45.

[139] E. E. Er, M. Valiente, K. Ganesh, et al., “Pericyte-Like Spreading by Disseminated Cancer Cells Activates YAP and MRTF for Metastatic Colonization,” Nature Cell Biology 20, no. 8 (2018): 966–978.

[140] C. M. Ferrer, H. M. Cho, R. Boon, et al., “The Glutathione S-transferase Gstt1 Drives Survival and Dissemination in Metastases,” Nature Cell Biology 26, no. 6 (2024): 975–990.

[141] A. R. Moorman, E. K. Benitez, F. Cambuli, et al., “Progressive Plasticity During Colorectal Cancer Metastasis,” Nature (2024).

[142] S. J Serrano-Gomez, M. Maziveyi, and S. K Alahari, “Regulation of Epithelial-mesenchymal Transition Through Epigenetic and Post-translational Modifications,” Molecular Cancer 15 (2016): 18.

[143] M. Gu, B. Ren, Y. Fang, et al., “Epigenetic Regulation in Cancer,” MedComm 5, no. 2 (2020): e495.

[144] M. Jakab, K. H. Lee, A. Uvarovskii, et al., “Lung Endothelium Exploits Susceptible Tumor Cell States to Instruct Metastatic Latency,” Nature Cancer 5, no. 5 (2024): 716–730.

[145] P. Peng, S. Qin, L. Li, et al., “Epigenetic Remodeling Under Oxidative Stress: Mechanisms Driving Tumor Metastasis,” MedComm—Oncology 3, no. 4 (2024): e70000.

[146] K. Ganesh and J. Massagué, “Targeting Metastatic Cancer,” Nature Medicine 27, no. 1 (2021): 34–44.

[147] F. Vidal-Vanaclocha, O. Crende, C. García de Durango, et al., “Liver Prometastatic Reaction: Stimulating Factors and Responsive Cancer Phenotypes,” Seminars in Cancer Biology 71 (2021): 122–133.

[148] P. Cheng, J. Wu, G. Zong, et al., “Capsaicin Shapes Gut Microbiota and Pre-metastatic Niche to Facilitate Cancer Metastasis to Liver,” Pharmacological Research 188 (2023): 106643.

[149] T. Teratani, Y. Mikami, N. Nakamoto, et al., “The Liver-brain-gut Neural Arc Maintains the T(reg) Cell Niche in the Gut,” Nature 585, no. 7826 (2020): 591–596.

[150] C. V. Odom, Y. Kim, C. L. Burgess, et al., “Liver-Dependent Lung Remodeling During Systemic Inflammation Shapes Responses to Secondary Infection,” Journal of Immunology 207, no. 7 (2021): 1891–1902.

[151] T. Aoyama, K. Kuwahara-Arai, A. Uchiyama, et al., “Spleen-derived Lipocalin-2 in the Portal Vein Regulates Kupffer Cells Activation and Attenuates the Development of Liver Fibrosis in Mice,” Laboratory Investigation 97, no. 8 (2017): 890–902.

[152] S. Anand and S. S Mande, “Host-microbiome Interactions: Gut-Liver Axis and Its Connection With Other Organs,” Npj Biofilms and Microbiomes 8, no. 1 (2022): 89.

[153] S. Hiratsuka, T. Tomita, T. Mishima, et al., “Hepato-Entrained B220(+)CD11c(+)NK1.1(+) Cells Regulate Pre-metastatic Niche Formation in the Lung,” EMBO Molecular Medicine 10, no. 7 (2018): e8643.

[154] Q. Li, X. X. Zhang, L. P. Hu, et al., “Coadaptation Fostered by the SLIT2-ROBO1 Axis Facilitates Liver Metastasis of Pancreatic Ductal Adenocarcinoma,” Nature Communications 14, no. 1 (2023): 861.

[155] B. Seubert, B. Grünwald, J. Kobuch, et al., “Tissue Inhibitor of Metalloproteinases (TIMP)-1 Creates a Premetastatic Niche in the Liver Through SDF-1/CXCR4-dependent Neutrophil Recruitment in Mice,” Hepatology 61, no. 1 (2015): 238–248.

[156] J. W. Lee, M. L. Stone, P. M. Porrett, et al., “Hepatocytes Direct the Formation of a Pro-metastatic Niche in the Liver,” Nature 567, no. 7747 (2019): 249–252.

[157] X. Yang, Y. Zhang, Y. Zhang, et al., “Colorectal Cancer-derived Extracellular Vesicles Induce Liver Premetastatic Immunosuppressive Niche Formation to Promote Tumor Early Liver Metastasis,” Signal Transduction and Targeted Therapy 8, no. 1 (2023): 102.

[158] Y. Cui, Y. Chang, X. Ma, et al., “Ephrin A1 Stimulates CCL2 Secretion to Facilitate Pre-metastatic Niche Formation and Promote Gastric Cancer Liver Metastasis,” Cancer Research (2024).

[159] D. Wang, H. Sun, J. Wei, et al., “CXCL1 Is Critical for Premetastatic Niche Formation and Metastasis in Colorectal Cancer,” Cancer Research 77, no. 13 (2017): 3655–3665.

[160] B. Costa-Silva, N. M. Aiello, A. J. Ocean, et al., “Pancreatic Cancer Exosomes Initiate Pre-metastatic Niche Formation in the Liver,” Nature Cell Biology 17, no. 6 (2015): 816–826.

[161] L. Xie, S. Qiu, C. Lu, et al., “Gastric Cancer-derived LBP Promotes Liver Metastasis by Driving Intrahepatic Fibrotic Pre-metastatic Niche Formation,” Journal of Experimental & Clinical Cancer Research 42, no. 1 (2023): 258.

[162] L. Chen, H. Zheng, X. Yu, et al., “Tumor-Secreted GRP78 Promotes the Establishment of a Pre-metastatic Niche in the Liver Microenvironment,” Frontiers in Immunology 11 (2020): 584458.

[163] Z. Zeng, Y. Li, Y. Pan, et al., “Cancer-derived Exosomal miR-25-3p Promotes Pre-metastatic Niche Formation by Inducing Vascular Permeability and Angiogenesis,” Nature Communications 9, no. 1 (2018): 5395.

[164] S. Zhao, Y. Mi, B. Zheng, 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,” Journal of Extracellular Vesicles 11, no. 1 (2022): e12186.

[165] B. Li, Y. Xia, J. Lv, et al., “miR-151a-3p-rich Small Extracellular Vesicles Derived From Gastric Cancer Accelerate Liver Metastasis via Initiating a Hepatic Stemness-enhancing Niche,” Oncogene 40, no. 43 (2021): 6180–6194.

[166] Y. Shao, T. Chen, X. Zheng, et al., “Colorectal Cancer-derived Small Extracellular Vesicles Establish an Inflammatory Premetastatic Niche in Liver Metastasis,” Carcinogenesis 39, no. 11 (2018): 1368–1379.

[167] H. Sun, Q. Meng, C. Shi, et al., “Hypoxia-Inducible Exosomes Facilitate Liver-Tropic Premetastatic Niche in Colorectal Cancer,” Hepatology 74, no. 5 (2021): 2633–2651.

[168] S. Zhao, Y. Mi, B. Guan, et al., “Tumor-derived Exosomal miR-934 Induces Macrophage M2 Polarization to Promote Liver Metastasis of Colorectal Cancer,” Journal of Hematology & Oncology 13, no. 1 (2020): 156.

[169] S. Qiu, L. Xie, C. Lu, et al., “Gastric Cancer-derived Exosomal miR-519a-3p Promotes Liver Metastasis by Inducing Intrahepatic M2-Like Macrophage-mediated Angiogenesis,” Journal of Experimental & Clinical Cancer Research 41, no. 1 (2022): 296.

[170] M. X. Li, S. Hu, H. H. Lei, et al., “Tumor-derived miR-9-5p-loaded EVs Regulate Cholesterol Homeostasis to Promote Breast Cancer Liver Metastasis in Mice,” Nature Communications 15, no. 1 (2024): 10539.

[171] W. Chen, W. Peng, R. Wang, et al., “Exosome-derived tRNA Fragments tRF-GluCTC-0005 Promotes Pancreatic Cancer Liver Metastasis by Activating Hepatic Stellate Cells,” Cell Death & Disease 15, no. 1 (2024): 102.

[172] A. Hoshino, B. Costa-Silva, T. L. Shen, et al., “Tumour Exosome Integrins Determine Organotropic Metastasis,” Nature 527, no. 7578 (2015): 329–335.

[173] Q. Ji, L. Zhou, H. Sui, et al., “Primary Tumors Release ITGBL1-rich Extracellular Vesicles to Promote Distal Metastatic Tumor Growth Through Fibroblast-niche Formation,” Nature Communications 11, no. 1 (2020): 1211.

[174] J. Zhou, Q. Song, H. Li, et al., “Targeting Circ-0034880-enriched Tumor Extracellular Vesicles to Impede SPP1(high)CD206(+) Pro-tumor Macrophages Mediated Pre-metastatic Niche Formation in Colorectal Cancer Liver Metastasis,” Molecular Cancer 23, no. (1) (2024): 168.

[175] C. Zhang, X. Y. Wang, P. Zhang, et al., “Cancer-derived Exosomal HSPC111 Promotes Colorectal Cancer Liver Metastasis by Reprogramming Lipid Metabolism in Cancer-associated Fibroblasts,” Cell Death & Disease 13, no. 1 (2022): 57.

[176] S. Pfeiler, M. Thakur, P. Grünauer, et al., “CD36-triggered Cell Invasion and Persistent Tissue Colonization by Tumor Microvesicles During Metastasis,” FASEB Journal 33, no. 2 (2019): 1860–1872.

[177] Z. Xie, Y. Gao, C. Ho, et al., “Exosome-delivered CD44v6/C1QBP Complex Drives Pancreatic Cancer Liver Metastasis by Promoting Fibrotic Liver Microenvironment,” Gut 71, no. 3 (2022): 568–579.

[178] C. Dudgeon, A. Casabianca, C. Harris, et al., “Netrin-1 Feedforward Mechanism Promotes Pancreatic Cancer Liver Metastasis via Hepatic Stellate Cell Activation, Retinoid, and ELF3 Signaling,” Cell Reports 42, no. 11 (2023): 113369.

[179] K. Jiang, H. Chen, Y. Fang, et al., “Exosomal ANGPTL1 Attenuates Colorectal Cancer Liver Metastasis by Regulating Kupffer Cell Secretion Pattern and Impeding MMP9 Induced Vascular Leakiness,” Journal of Experimental & Clinical Cancer Research 40, no. 1 (2021): 21.

[180] I. Wortzel, Y. Seo, I. Akano, et al., “Unique Structural Configuration of EV-DNA Primes Kupffer Cell-mediated Antitumor Immunity to Prevent Metastatic Progression,” Nat Cancer. 2024.

[181] S. Takesue, K. Ohuchida, T. Shinkawa, et al., “Neutrophil Extracellular Traps Promote Liver Micrometastasis in Pancreatic Ductal Adenocarcinoma via the Activation of Cancer-Associated Fibroblasts,” International Journal of Oncology 56, no. 2 (2020): 596–605.

[182] J. Albrengues, M. A. Shields, D. Ng, et al., “Neutrophil Extracellular Traps Produced During Inflammation Awaken Dormant Cancer Cells in Mice,” Science 361 no. 6409 (2018): eaao4227.

[183] X. Qiu, J. Zhou, H. Xu, et al., “Alcohol Reshapes a Liver Premetastatic Niche for Cancer by Extra-and Intrahepatic Crosstalk-mediated Immune Evasion,” Molecular Therapy 31, no. 9 (2023): 2662–2680.

[184] S. Parida, S. Siddharth, H. R. Gatla, et al., “Gut Colonization With an Obesity-associated Enteropathogenic Microbe Modulates the Premetastatic Niches to Promote Breast Cancer Lung and Liver Metastasis,” Frontiers in Immunology 14, (2023): 1194931.

[185] Y. Shigematsu, R. Saito, G. Amori, et al., “Fusobacterium nucleatum, Immune Responses, and Metastatic Organ Diversity in Colorectal Cancer Liver Metastasis,” Cancer Science 115, no. 10 (2024): 3248–3255.

[186] A. Bertocchi, S. Carloni, P. S. Ravenda, et al., “Gut Vascular Barrier Impairment Leads to Intestinal Bacteria Dissemination and Colorectal Cancer Metastasis to Liver,” Cancer Cell 39, no. 5 (2021): 708-724.

[187] Q. Zhan, B. Liu, X. Situ, et al., “New Insights Into the Correlations Between Circulating Tumor Cells and Target Organ Metastasis,” Signal Transduction Target Therapy 8, no. 1 (2023): 465.

[188] X. Liu, J. Song, H. Zhang, et al., “Immune Checkpoint HLA-E:CD94-NKG2A Mediates Evasion of Circulating Tumor Cells From NK Cell Surveillance,” Cancer Cell 41, no. 2 (2023): 272-287.

[189] L. N. Qi, B. D. Xiang, F. X. Wu, et al., “Circulating Tumor Cells Undergoing EMT Provide a Metric for Diagnosis and Prognosis of Patients With Hepatocellular Carcinoma,” Cancer Research 78, no. 16 (2018): 4731–4744.

[190] B. Hamza, A. B. Miller, L. Meier, et al., “Measuring Kinetics and Metastatic Propensity of CTCs by Blood Exchange Between Mice,” Nature Communications 12, no. 1 (2021): 5680.

[191] H. Zhang, N. Yang, B. Sun, et al., “CD133 positive Cells Isolated From A549 Cell Line Exhibited High Liver Metastatic Potential,” Neoplasma 61, no. 2 (2014): 153–160.

[192] Z. Wu, D. Wei, W. Gao, et al., “TPO-Induced Metabolic Reprogramming Drives Liver Metastasis of Colorectal Cancer CD110+ Tumor-Initiating Cells,” Cell Stem Cell 17, no. 1 (2015): 47–59.

[193] M. Li, S. Wu, C. Zhuang, et al., “Metabolomic Analysis of Circulating Tumor Cells Derived Liver Metastasis of Colorectal Cancer,” Heliyon 2023; 9(1):e12515.

[194] Q. Lin, X. Chen, F. Meng, et al., “ASPH-notch Axis Guided Exosomal Delivery of Prometastatic Secretome Renders Breast Cancer Multi-organ Metastasis,” Molecular Cancer 18, no. 1 (2019): 156.

[195] R. Izutsu, M. Osaki, H. Nemoto, et al., “AMIGO2 contained in Cancer Cell-derived Extracellular Vesicles Enhances the Adhesion of Liver Endothelial Cells to Cancer Cells,” Scientific Reports 12, no. 1 (2022): 792.

[196] G. Bagci, D. Comez, H. Topel, et al., “c-Met Activation Promotes Extravasation of Hepatocellular Carcinoma Cells Into 3D-cultured Hepatocyte Cells in Lab-on-a-chip Device,” Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1870, no. 8 (2023): 119557.

[197] S. Chen, Y. Wu, Y. Gao, et al., “Allosterically Inhibited PFKL via Prostaglandin E2 Withholds Glucose Metabolism and Ovarian Cancer Invasiveness,” Cell Reports 42, no. 10 (2023): 113246.

[198] C.-Y. Liao, G. Li, F.-P. Kang, et al., “Necroptosis Enhances ‘Don’t Eat Me’ signal and Induces Macrophage Extracellular Traps to Promote Pancreatic Cancer Liver Metastasis,” Nature Communications 15, no. 1 (2024): 6043.

[199] K. Lei, M. Sun, X. Chen, et al., “hnRNPAB Promotes Pancreatic Ductal Adenocarcinoma Extravasation and Liver Metastasis by Stabilizing MYC mRNA,” Molecular Cancer Research 22, no. 11 (2024): 1022–1035.

[200] H. Kajioka, S. Kagawa, A. Ito, et al., “Targeting Neutrophil Extracellular Traps With Thrombomodulin Prevents Pancreatic Cancer Metastasis,” Cancer Letters 497 (2021): 1–13.

[201] X. Xia, Z. Zhang, C. Zhu, et al., “Neutrophil Extracellular Traps Promote Metastasis in Gastric Cancer Patients With Postoperative Abdominal Infectious Complications,” Nature Communications 13, no. 1 (2022): 1017.

[202] F. Marchesi, P. Monti, B. E. Leone, et al., “Increased Survival, Proliferation, and Migration in Metastatic human Pancreatic Tumor Cells Expressing Functional CXCR4,” Cancer Research 64, no. 22 (2004): 8420–8427.

[203] C. Tian, D. Öhlund, S. Rickelt, et al., “Cancer Cell-Derived Matrisome Proteins Promote Metastasis in Pancreatic Ductal Adenocarcinoma,” Cancer Research 80, no. 7 (2020): 1461–1474.

[204] C. Ren, Z. Yang, E. Xu, et al., “Cross-talk Between Gastric Cancer and Hepatic Stellate Cells Promotes Invadopodia Formation During Liver Metastasis,” Cancer Science 115, no. 2 (2024): 369–384.

[205] S. Qi, S. Perrino, X. Miao, et al., “The Chemokine CCL7 Regulates Invadopodia Maturation and MMP-9 Mediated Collagen Degradation in Liver-metastatic Carcinoma Cells,” Cancer Letters 483 (2020): 98–113.

[206] J. Laferrière, F. Houle, and J. Huot, “Adhesion of HT-29 Colon Carcinoma Cells to Endothelial Cells Requires Sequential Events Involving E-selectin and Integrin beta4,” Clinical & Experimental Metastasis 21, no. (3) (2004): 257–264.

[207] N. Osmani, G. Follain, M. J. García León, et al., “Metastatic Tumor Cells Exploit Their Adhesion Repertoire to Counteract Shear Forces During Intravascular Arrest,” Cell Reports 28, no. 10 (2019): 2491-2500.

[208] L. A. Coupland, B. H. Chong, and C. R Parish, “Platelets and P-selectin Control Tumor Cell Metastasis in an Organ-specific Manner and Independently of NK Cells,” Cancer Research 72, no. 18 (2012): 4662–4671.

[209] H. Li, Y. Hu, and Y. Jin, et al., “Long Noncoding RNA lncGALM Increases Risk of Liver Metastasis in Gallbladder Cancer Through Facilitating N-cadherin and IL-1β-dependent Liver Arrest and Tumor Extravasation,” Clinical and Translational Medicine 10, no. 7 (2020): e201.

[210] T. Huu Hoang, M. Sato-Matsubara, H. Yuasa, et al., “Cancer Cells Produce Liver Metastasis via Gap Formation in Sinusoidal Endothelial Cells Through Proinflammatory Paracrine Mechanisms,” Science Advances 2022; 8(39):eabo5525.

[211] A. D. Giannou, J. Kempski, A. M. Shiri, et al., “Tissue Resident iNKT17 Cells Facilitate Cancer Cell Extravasation in Liver Metastasis via Interleukin-22,” Immunity 56, no. 1 (2023): 125-142.

[212] K. Liao, X. Zhang, J. Liu, et al., “The Role of Platelets in the Regulation of Tumor Growth and Metastasis: The Mechanisms and Targeted Therapy,” MedComm 4, no. 5 (2020): e350.

[213] A. Takemoto, M. Okitaka, S. Takagi, et al., “A Critical Role of Platelet TGF-β Release in Podoplanin-Mediated Tumour Invasion and Metastasis,” Scientific Reports 7 (2017): 42186.

[214] D. Schumacher, B. Strilic, K. K. Sivaraj, et al., “Platelet-derived Nucleotides Promote Tumor-cell Transendothelial Migration and Metastasis via P2Y2 Receptor,” Cancer Cell 24, no. 1 (2013): 130–137.

[215] C.-M. Lee, M.-L. Chang, R.-H. Chen, et al., “Thrombin-Activated Platelets Protect Vascular Endothelium Against Tumor Cell Extravasation by Targeting Endothelial VCAM-1,” International Journal of Molecular Sciences 23, no. 7 (2022): 3433.

[216] M. A. Summers, M. M. McDonald, and P. I. Croucher, “Cancer Cell Dormancy in Metastasis,” Cold Spring Harbor Perspectives in Medicine 10, no. 4 (2020).

[217] A. L. Correia, J. C. Guimaraes, P. Auf der Maur, et al., “Hepatic Stellate Cells Suppress NK Cell-sustained Breast Cancer Dormancy,” Nature 594, no. 7864 (2021): 566–571.

[218] R. D. Schreiber, L. J. Old, and M. J Smyth., “Cancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and Promotion,” Science 331, no. 6024 (2011): 1565–1570.

[219] T. Zhang, J. Chen, H. Yang, et al., “Stromal Softness Confines Pancreatic Cancer Growth Through Lysosomal-cathepsin Mediated YAP1 Degradation,” Cellular and Molecular Life Sciences 2024; 81(1): 442.

[220] L. Miarka, C. Hauser, O. Helm, et al., “The Hepatic Microenvironment and TRAIL-R2 Impact Outgrowth of Liver Metastases in Pancreatic Cancer After Surgical Resection,” Cancers (Basel) 11, no. 6 (2019): 745.

[221] A. Fabian, S. Stegner, L. Miarka, et al., “Metastasis of Pancreatic Cancer: An Uninflamed Liver Micromilieu Controls Cell Growth and Cancer Stem Cell Properties by Oxidative Phosphorylation in Pancreatic Ductal Epithelial Cells,” Cancer Letters 453, (2019): 95–106.

[222] C. D’Alterio, S. Scala, G. Sozzi, et al., “Paradoxical Effects of Chemotherapy on Tumor Relapse and Metastasis Promotion,” Seminars in Cancer Biology 60 (2020): 351–361.

[223] N. Sakai, K. Hayano, T. Mishima, et al., “Fat Signal Fraction Assessed With MRI Predicts Hepatic Recurrence Following Hepatic Resection for Colorectal Liver Metastases,” Langenbecks Archives of Surgery 407, no. 5 (2022): 1981–1989.

[224] M. R. Shurin, J. H. Baraldi, and G. V. Shurin, “Neuroimmune Regulation of Surgery-Associated Metastases,” Cells 10, no. 2 (2021): 454.

[225] J. Hu, F. J. Sánchez-Rivera, Z. Wang, et al., “STING Inhibits the Reactivation of Dormant Metastasis in Lung Adenocarcinoma,” Nature 616, no. 7958 (2023): 806–813.

[226] D. B. Fox, N. M. G. Garcia, B. J. McKinney, et al., “NRF2 activation Promotes the Recurrence of Dormant Tumour Cells Through Regulation of Redox and Nucleotide Metabolism,” Nature Metabolism 2, no. 4 (2020): 318–334.

[227] L. E. Barney, C. L. Hall, A. D. Schwartz, et al., “Tumor Cell-organized Fibronectin Maintenance of a Dormant Breast Cancer Population,” Science Advances 6, no. 11 (2020): eaaz4157.

[228] C. M. Ghajar, H. Peinado, H. Mori, et al., “The Perivascular Niche Regulates Breast Tumour Dormancy,” Nature Cell Biology 15, no. 7 (2013): 807–817.

[229] G. G. Van den Eynden, N. C. Bird, A. W. Majeed, et al., “The Histological Growth Pattern of Colorectal Cancer Liver Metastases Has Prognostic Value,” Clinical & Experimental Metastasis 29, no. 6 (2012): 541–549.

[230] C. F. Moro, N. Geyer, and S. Harrizi, et al., “An Idiosyncratic Zonated Stroma Encapsulates Desmoplastic Liver Metastases and Originates From Injured Liver,” Nature Communications 14, no. 1 (2023): 5024.

[231] E. Cambria, M. F. Coughlin, M. A. Floryan, et al., “Linking Cell Mechanical Memory and Cancer Metastasis,” Nature Reviews Cancer 24, no. 3 (2024): 216–228.

[232] S. Paku and K. Lapis, “Morphological Aspects of Angiogenesis in Experimental Liver Metastases,” American Journal of Pathology 143, no. 3 (1993): 926–936.

[233] O. R. Mook, J. van Marle, R. Jonges, et al., “Interactions Between Colon Cancer Cells and Hepatocytes in Rats in Relation to Metastasis,” Journal of Cellular and Molecular Medicine 12, no. 5b (2008): 2052–2061.

[234] S. Tabariès, F. Dupuy, Z. Dong, et al., “Claudin-2 Promotes Breast Cancer Liver Metastasis by Facilitating Tumor Cell Interactions With Hepatocytes,” Molecular and Cellular Biology 32, no. 15 (2012): 2979–2991.

[235] C. Borrelli, M. Roberts, D. Eletto, et al., “In Vivo Interaction Screening Reveals Liver-derived Constraints to Metastasis,” Nature 632, no. 8024 (2024): 411–418.

[236] S. Zhou, K. Yang, S. Chen, et al., “CCL3 secreted by Hepatocytes Promotes the Metastasis of Intrahepatic Cholangiocarcinoma by VIRMA-mediated N6-methyladenosine (m(6)A) Modification,” Journal of Translational Medicine 21, no. 1 (2023): 43.

[237] L. Long, J. Nip, and P. Brodt, “Paracrine Growth Stimulation by Hepatocyte-derived Insulin-Like Growth Factor-1: A Regulatory Mechanism for Carcinoma Cells Metastatic to the Liver,” Cancer Research 54, no. 14 (1994): 3732–3737.

[238] Y. Li, X. Su, N. Rohatgi, et al., “Hepatic Lipids Promote Liver Metastasis,” JCI Insight 5, no. 17 (2020): e136215.

[239] X. Li, Z. Wang, C. Jiao, et al., “Hepatocyte SGK1 Activated by Hepatic Ischemia-reperfusion Promotes the Recurrence of Liver Metastasis via IL-6/STAT3,” Journal of Translational Medicine 21, no. 1 (2023): 121.

[240] L. Wu, J. Yan, Y. Bai, et al., “An Invasive Zone in human Liver Cancer Identified by Stereo-seq Promotes Hepatocyte-tumor Cell Crosstalk, Local Immunosuppression and Tumor Progression,” Cell Research 33, no. 8 (2023): 585–603.

[241] F. Xi, H. Sun, H. Peng, et al., “Hepatocyte-derived FGL1 Accelerates Liver Metastasis and Tumor Growth by Inhibiting CD8+ T and NK Cells,” JCI Insight 9, no. 13 (2024) e173215.

[242] M. Pucci, M. Moschetti, O. Urzì, et al., “Colorectal Cancer-derived Small Extracellular Vesicles Induce TGFβ1-mediated Epithelial to Mesenchymal Transition of Hepatocytes,” Cancer Cell International 23, no. 1 (2023): 77.

[243] K. F. Yoong, S. C. Afford, S. Randhawa, et al., “Fas/Fas Ligand Interaction in human Colorectal Hepatic Metastases: A Mechanism of Hepatocyte Destruction to Facilitate Local Tumor Invasion,” American Journal of Pathology 154, no. 3 (1999): 693–703.

[244] Q. Zhao, M. D. P. Molina-Portela, A. Parveen, et al., “Heterogeneity and Chimerism of Endothelial Cells Revealed by Single-cell Transcriptome in Orthotopic Liver Tumors,” Angiogenesis 23, no. 4 (2020): 581–597.

[245] A. Benedicto, A. Herrero, I. Romayor, et al., “Liver Sinusoidal Endothelial Cell ICAM-1 Mediated Tumor/Endothelial Crosstalk Drives the Development of Liver Metastasis by Initiating Inflammatory and Angiogenic Responses,” Scientific Reports 9, no. 1 (2019): 13111.

[246] H. Na, X. Liu, X. Li, et al., “Novel Roles of DC-SIGNR in Colon Cancer Cell Adhesion, Migration, Invasion, and Liver Metastasis,” Journal of Hematology & Oncology 10, no. 1 (2017): 28.

[247] K. Kato, T. Noda, S. Kobayashi, et al., “KLK10 derived From Tumor Endothelial Cells Accelerates Colon Cancer Cell Proliferation and Hematogenous Liver Metastasis Formation,” Cancer Science 115, no. 5 (2024): 1520–1535.

[248] J. Ou, Y. Peng, J. Deng, et al., “Endothelial Cell-derived Fibronectin Extra Domain A Promotes Colorectal Cancer Metastasis via Inducing Epithelial-mesenchymal Transition,” Carcinogenesis 35, no. 7 (2014): 1661–1670.

[249] L. Ma, X. He, Y. Fu, et al., “Senescent Endothelial Cells Promote Liver Metastasis of Uveal Melanoma in Single-cell Resolution,” Journal of Translational Medicine 22, no. 1 (2024): 605.

[250] A. S. Jauch, S. A. Wohlfeil, C. Weller, et al., “Lyve-1 Deficiency Enhances the Hepatic Immune Microenvironment Entailing Altered Susceptibility to Melanoma Liver Metastasis,” Cancer Cell International 22, no. 1 (2022): 398.

[251] C. Li, T. Chen, J. Liu, et al., “FGF19-Induced Inflammatory CAF Promoted Neutrophil Extracellular Trap Formation in the Liver Metastasis of Colorectal Cancer,” Advanced science (Weinheim, Baden-Württemberg, Germany) 10, no. 24 (2023): e2302613.

[252] K. Tu, J. Li, V. K. Verma, et al., “Vasodilator-stimulated Phosphoprotein Promotes Activation of Hepatic Stellate Cells by Regulating Rab11-dependent Plasma Membrane Targeting of Transforming Growth Factor Beta Receptors,” Hepatology 61, no. 1 (2015): 361–374.

[253] E. Olaso, C. Salado, E. Egilegor, et al., “Proangiogenic Role of Tumor-activated Hepatic Stellate Cells in Experimental Melanoma Metastasis,” Hepatology 37, no. 3 (2003): 674–685.

[254] C. Dou, Z. Liu, K. Tu, et al., “P300 Acetyltransferase Mediates Stiffness-Induced Activation of Hepatic Stellate Cells into Tumor-Promoting Myofibroblasts,” Gastroenterology 154, no. 8 (2018): 2209–2221.

[255] M. Qi, S. Fan, M. Huang, et al., “Targeting FAPα-expressing Hepatic Stellate Cells Overcomes Resistance to Antiangiogenics in Colorectal Cancer Liver Metastasis Models,” Journal of Clinical Investigation 132, no. 19 (2022): e157399.

[256] D. Ezhilarasan, “Hepatic Stellate Cells in the Injured Liver: Perspectives Beyond Hepatic Fibrosis,” Journal of Cellular Physiology 237, no. 1 (2022): 436–449.

[257] S. W. Wen, E. I. Ager, and C. Christophi, “Bimodal Role of Kupffer Cells During Colorectal Cancer Liver Metastasis,” Cancer Biology & Therapy 14, no. 7 (2013): 606–613.

[258] Y. Kimura, A. Inoue, S. Hangai, et al., “The Innate Immune Receptor Dectin-2 Mediates the Phagocytosis of Cancer Cells by Kupffer Cells for the Suppression of Liver Metastasis,” Proceedings of the National Academy of Sciences of the United States of America 113, no. 49 (2016): 14097–14102.

[259] J. Li, X. G. Liu, R. L. Ge, et al., “The Ligation Between ERMAP, Galectin-9 and Dectin-2 Promotes Kupffer Cell Phagocytosis and Antitumor Immunity,” Nature Immunology 24, no. 11 (2023): 1813–1824.

[260] E. Song, J. Chen, N. Ouyang, et al., “Kupffer Cells of Cirrhotic Rat Livers Sensitize Colon Cancer Cells to Fas-mediated Apoptosis,” British Journal of Cancer 84, no. 9 (2001): 1265–1271.

[261] W. Y. Lau, G. G. Chen, P. B. Lai, et al., “Induction of Fas and Fas Ligand Expression on Malignant Glioma Cells by Kupffer Cells, a Potential Pathway of Antiliver Metastases,” Journal of Surgical Research 101, no. 1 (2001): 44–51.

[262] Y. Yang, Y. Chen, Z. Liu, et al., “Concomitant NAFLD Facilitates Liver Metastases and PD-1-Refractory by Recruiting MDSCs via CXCL5/CXCR2 in Colorectal Cancer,” Cellular Molecular Gastroenterology Hepatology 18, no. 2 (2024): 101351.

[263] N. Yuan, X. Li, M. Wang, et al., “Gut Microbiota Alteration Influences Colorectal Cancer Metastasis to the Liver by Remodeling the Liver Immune Microenvironment,” Gut Liver 16, no. 4 (2022): 575–588.

[264] M. H. Sieweke and J. E Allen, “Beyond Stem Cells: Self-renewal of Differentiated Macrophages,” Science 342, no. 6161 (2013): 1242974.

[265] S. K. Thomas, M. M. Wattenberg, S. Choi-Bose, et al., “Kupffer Cells Prevent Pancreatic Ductal Adenocarcinoma Metastasis to the Liver in Mice,” Nature Communications 14, no. 1 (2023): 6330.

[266] W. Liu, X. Zhou, Q. Yao, et al., “In Situ Expansion and Reprogramming of Kupffer Cells Elicit Potent Tumoricidal Immunity Against Liver Metastasis,” Journal of Clinical Investigation 133, no. 8 (2023): e157937.

[267] H. Qin, A. Xiao, Q. Lu, et al., “The Fatty Acid Receptor CD36 Promotes Macrophage Infiltration via p110γ Signaling to Stimulate Metastasis,” Journal of Advanced Research (2024).

[268] D. Wang, X. Wang, M. Si, et al., “Exosome-encapsulated miRNAs Contribute to CXCL12/CXCR4-induced Liver Metastasis of Colorectal Cancer by Enhancing M2 Polarization of Macrophages,” Cancer Letters 474 (2020): 36–52.

[269] Y. Geng, J. Fan, and L. Chen, et al., “A Notch-Dependent Inflammatory Feedback Circuit Between Macrophages and Cancer Cells Regulates Pancreatic Cancer Metastasis,” Cancer Research 81, no. 1 (2021): 64–76.

[270] S. Dai, F. Xu, X. Xu, et al., “miR-455/GREM1 Axis Promotes Colorectal Cancer Progression and Liver Metastasis by Affecting PI3K/AKT Pathway and Inducing M2 Macrophage Polarization,” Cancer Cell International 24, no. 1 (2024): 235.

[271] X. L. Zhang, L. P. Hu, Q. Yang, et al., “CTHRC1 promotes Liver Metastasis by Reshaping Infiltrated Macrophages Through Physical Interactions With TGF-β Receptors in Colorectal Cancer,” Oncogene 40, no. 23 (2021): 3959–3973.

[272] B. Huang, Z. Yu, D. Cui, F. Du, “MAPKAP1 orchestrates Macrophage Polarization and Lipid Metabolism in Fatty Liver-enhanced Colorectal Cancer,” Translationa Oncology 45 (2024): 101941.

[273] M. Raymant, Y. Astuti, L. Alvaro-Espinosa, et al., “Macrophage-fibroblast JAK/STAT Dependent Crosstalk Promotes Liver Metastatic Outgrowth in Pancreatic Cancer,” Nature Communications 15, no. 1 (2024): 3593.

[274] Y. Astuti, M. Raymant, V. Quaranta, et al., “Efferocytosis Reprograms the Tumor Microenvironment to Promote Pancreatic Cancer Liver Metastasis,” Nature Cancer 5, no. 5 (2024): 774–790.

[275] J. Gu, X. Xu, X. Li, et al., “Tumor-resident Microbiota Contributes to Colorectal Cancer Liver Metastasis by Lactylation and Immune Modulation,” Oncogene 43, no. 31 (2024): 2389–2404.

[276] W. Chen, M. Zhou, B. Guan, et al., “Tumour-associated Macrophage-derived DOCK7-enriched Extracellular Vesicles Drive Tumour Metastasis in Colorectal Cancer via the RAC1/ABCA1 Axis,” Clinical and Translational Medicine 14, no. 2 (2024): e1591.

[277] B. Ni, X. He, Y. Zhang, et al., “Tumor-associated Macrophage-derived GDNF Promotes Gastric Cancer Liver Metastasis via a GFRA1-modulated Autophagy Flux,” Cellular Oncoogyl (Dordr) 46, no. 2 (2023): 315–330.

[278] Y. Du, Y. Lin, L. Gan, et al., “Potential Crosstalk Between SPP1 + TAMs and CD8 + Exhausted T Cells Promotes an Immunosuppressive Environment in Gastric Metastatic Cancer,” Journal of Translational Medicine 22, no. 1 (2024): 158.

[279] Y. Sun, H. Hu, Z. Liu, et al., “Macrophage STING Signaling Promotes NK Cell to Suppress Colorectal Cancer Liver Metastasis via 4-1BBL/4-1BB co-stimulation,” Journal for Immunotherapy of Cancer 11, no. 3 (2023); e006481.

[280] L. Zhao, D. Zhang, Q. Shen, et al., “KIAA1199 promotes Metastasis of Colorectal Cancer Cells Via Microtubule Destabilization Regulated by a PP2A/Stathmin Pathway,” Oncogene 38, no. 7 (2019): 935–949.

[281] J. Zhou, W. Xu, Y. Wu, et al., “GPR37 promotes Colorectal Cancer Liver Metastases by Enhancing the Glycolysis and Histone Lactylation via Hippo Pathway,” Oncogene 42, no. 45 (2023): 3319–3330.

[282] T. Luckett, M. Abudula, L. Ireland, et al., “Mesothelin Secretion by Pancreatic Cancer Cells Co-opts Macrophages and Promotes Metastasis,” Cancer Research 84, no. 4 (2024): 527–544.

[283] Y. Huo, Y. Zhou, J. Zheng, et al., “GJB3 promotes Pancreatic Cancer Liver Metastasis by Enhancing the Polarization and Survival of Neutrophil,” Frontiers in Immunology 13 (2022): 983116.

[284] L. Sun, N. Yang, Z. Liu, et al., “Cholestasis-induced Phenotypic Transformation of Neutrophils Contributes to Immune Escape of Colorectal Cancer Liver Metastasis,” Journal of Biomedical Science 31, no. 1 (2024): 66.

[285] D. Rao, J. Li, M. Zhang, et al., “Multi-model Analysis of Gallbladder Cancer Reveals the Role of OxLDL-absorbing Neutrophils in Promoting Liver Invasion,” Experimental Hematology & Oncology 13, no. 1 (2024): 58.

[286] G. Bellomo, C. Rainer, V. Quaranta, et al., “Chemotherapy-induced Infiltration of Neutrophils Promotes Pancreatic Cancer Metastasis via Gas6/AXL Signalling Axis,” Gut 71, no. 11 (2022): 2284–2299.

[287] S. Tian, Y. Chu, J. Hu, et al., “Tumour-associated Neutrophils Secrete AGR2 to Promote Colorectal Cancer Metastasis via Its Receptor CD98hc-xCT,” Gut 71, no. 12 (2022): 2489–2501.

[288] X. Wang, L. P. Hu, W. T. Qin, et al., “Identification of a Subset of Immunosuppressive P2RX1-negative Neutrophils in Pancreatic Cancer Liver Metastasis,” Nature Communications 12, no. 1 (2021): 174.

[289] D. Vermijlen, D. Luo, B. Robaye, et al., “Pit Cells (Hepatic natural killer cells) of the Rat Induce Apoptosis in Colon Carcinoma Cells by the Perforin/Granzyme Pathway,” Hepatology 29, no. 1 (1999): 51–56.

[290] J. Zhao, H. A. Schlößer, Z. Wang, et al., “Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer,” Cancers (Basel) 11, no. 6 (2019): 874.

[291] X. Tang, L. Gao, X. Jiang, et al., “Single-cell Profiling Reveals Altered Immune Landscape and Impaired NK Cell Function in Gastric Cancer Liver Metastasis,” Oncogene 43, no. 35 (2024): 2635–2646.

[292] J. Song, H. Song, H. Wei, et al., “Requirement of RORα for Maintenance and Antitumor Immunity of Liver-resident Natural Killer Cells/ILC1s,” Hepatology 75, no. 5 (2022): 1181–1193.

[293] L. Patras, L. Shaashua, I. Matei, et al., “Immune Determinants of the Pre-metastatic Niche,” Cancer Cell 41, no. 3 (2023): 546–572.

[294] G. Sun, S. Zhao, Z. Fan, et al., “CHSY1 promotes CD8(+) T Cell Exhaustion Through Activation of Succinate Metabolism Pathway Leading to Colorectal Cancer Liver Metastasis Based on CRISPR/Cas9 Screening,” Journal of Experimental & Clinical Cancer Research 42, no. 1 (2023): 248.

[295] J. C. Lee, S. Mehdizadeh, J. Smith, et al., “Regulatory T Cell Control of Systemic Immunity and Immunotherapy Response in Liver Metastasis,” Science Immunology 5, no. 52 (2020): eaba0759.

[296] J. A. Kenkel, W. W. Tseng, M. G. Davidson, et al., “An Immunosuppressive Dendritic Cell Subset Accumulates at Secondary Sites and Promotes Metastasis in Pancreatic Cancer,” Cancer Research 77, no. 15 (2017): 4158–4170.

[297] T. N. Schumacher and D. S Thommen, “Tertiary Lymphoid Structures in Cancer,” Science 375, no. 6576 (2022): eabf9419.

[298] M. Lee, S. H. Heo, I. H. Song, et al., “Presence of Tertiary Lymphoid Structures Determines the Level of Tumor-infiltrating Lymphocytes in Primary Breast Cancer and Metastasis,” Modern Pathology 32, no. 1 (2019): 70–80.

[299] Y. Zhang, G. Liu, Q. Zeng, et al., “CCL19-producing Fibroblasts Promote Tertiary Lymphoid Structure Formation Enhancing Anti-tumor IgG Response in Colorectal Cancer Liver Metastasis,” Cancer Cells 42, no. 8 (2024): 1370-1385.

[300] A. Senk, J. Fazzari, and V. Djonov, “Vascular Mimicry in Zebrafish Fin Regeneration: How Macrophages Build New Blood Vessels,” Angiogenesis 27, no. 3 (2024): 397–410.

[301] C. K. Mo, J. Liu, S. Chen, et al., “Tumour Evolution and Microenvironment Interactions in 2D and 3D Space,” Nature 634, no. 8036 (2024): 1178–1186.

[302] B. Zheng, D. Wang, X. Qiu, et al., “Trajectory and Functional Analysis of PD-1(high) CD4(+)CD8(+) T Cells in Hepatocellular Carcinoma by Single-Cell Cytometry and Transcriptome Sequencing,” Advanced Science (Weinh) 7, no. 13 (2020): 2000224.

[303] J. Qi, H. Sun, Y. Zhang, et al., “Single-cell and Spatial Analysis Reveal Interaction of FAP(+) Fibroblasts and SPP1(+) Macrophages in Colorectal Cancer,” Nature Communications 13, no. 1 (2022): 1742.

[304] I. Yofe, T. Shami, N. Cohen, et al., “Spatial and Temporal Mapping of Breast Cancer Lung Metastases Identify TREM2 Macrophages as Regulators of the Metastatic Boundary,” Cancer Discovery 13, no. 12 (2023): 2610–2631.

[305] Y. He, Y. Han, A.-H. Fan, et al., “Multi-perspective Comparison of the Immune Microenvironment of Primary Colorectal Cancer and Liver Metastases,” Journal of Translational Medicine 20, no. 1 (2022): 454.

[306] S. Beckinger, T. Daunke, L. Aldag, et al., “Hepatic Myofibroblasts Exert Immunosuppressive Effects Independent of the Immune Checkpoint Regulator PD-L1 in Liver Metastasis of Pancreatic Ductal Adenocarcinoma,” Frontiers in Oncology 13 (2023): 1160824.

[307] K. Sideras, B. Galjart, A. Vasaturo, et al., “Prognostic Value of Intra-tumoral CD8(+) /FoxP3(+) Lymphocyte Ratio in Patients With Resected Colorectal Cancer Liver Metastasis,” Journal of Surgical Oncology 118, no. 1 (2018): 68–76.

[308] N. Cortese, R. Carriero, M. Barbagallo, et al., “High-Resolution Analysis of Mononuclear Phagocytes Reveals GPNMB as a Prognostic Marker in Human Colorectal Liver Metastasis,” Cancer Immunology Research 11, no. 4 (2023): 405–420.

[309] D. Jiang, A. Huang, B.-X. Zhu, et al., “Targeting CD93 on Monocytes Revitalizes Antitumor Immunity by Enhancing the Function and Infiltration of CD8(+) T Cells,” Journal for Immunotherapy of Cancer 12, no. 10 (2024): e010148.

[310] K. Medetgul-Ernar and M. M Davis, “Standing on the Shoulders of Mice,” Immunity 55, no. 8 (2022): 1343–1353.

[311] T. M. Pawlik and M. A Choti, “Surgical Therapy for Colorectal Metastases to the Liver,” Journal of Gastrointestinal Surgery 11, no. 8 (2007): 1057–1077.

[312] J. M. Cloyd, J. T. Wiseman, and T. M Pawlik, “Surgical Management of Pancreatic Neuroendocrine Liver Metastases,” Journal of Gastrointestinal Oncology 11, no. 3 (2020): 590–600.

[313] M. Yeo, Y. Masuda, M.-P. Calvo, M. D. Martino B. lelpo, K. Ye-Xin, “Surgery for Liver Metastases From Primary Melanoma: A Systematic Review and Meta-analysis,” Langenbecks Archives of Surgery 407, no. 8 (2022): 3235–3247.

[314] A. R. R Weiss, N. E. Donlon, H. J. Schlitt, C. Hackl, “Resection of Oesophageal and Oesophagogastric Junction Cancer Liver Metastases—a Summary of Current Evidence,” Langenbecks Archives of Surgery 407, no. 3 (2022): 947–955.

[315] A. Hamad, J. Underhill, A. Ansari, et al., “Surgical Treatment of Hepatic Oligometastatic Pancreatic Ductal Adenocarcinoma: An Analysis of the National Cancer Database,” Surgery 171, no. 6 (2022): 1464–1470.

[316] J. Baur, T. O. Büntemeyer, F. Megerle, et al., “Outcome After Resection of Adrenocortical Carcinoma Liver Metastases: A Retrospective Study,” BMC Cancer 17, no. 1 (2017): 522.

[317] L. Zhu, S. Gao, X. Wu, et al. Survival Outcomes of Conversion Surgery for Metastatic Pancreatic Ductal Adenocarcinoma After Neoadjuvant Therapy. 2023; 6(3): 110–118.

[318] P. C. Müller, M. Pfister, D. Eshmuminov, L. Kulo, et al., “Liver Transplantation as an Alternative for the Treatment of Neuroendocrine Liver Metastasis: Appraisal of the Current Evidence Hepatobiliary,” Hepatobiliary & Pancreatic Diseases International 23, no. 2 (2024): 146–153.

[319] J. Lanari, M. Hagness, A. Sartori, et al., “Liver Transplantation versus Liver Resection for Colorectal Liver Metastasis: A Survival Benefit Analysis in Patients Stratified According to Tumor Burden Score,” Transplant International 34, no. 9 (2021): 1722–1732.

[320] S. Grewal, S. J. Oosterling, and M. van Egmond, “Surgery for Colorectal Cancer: A Trigger for Liver Metastases Development? New Insights into the Underlying Mechanisms,” Biomedicines 9, no. 2 (2021): 177.

[321] X. Cheng, H. Zhang, A. Hamad, , A. Tsung, “Surgery-mediated Tumor-promoting Effects on the Immune Microenvironment,” Seminars in Cancer Biology 86, no. 3 (2022): 408–419.

[322] G. E. Riddiough, Q. Jalal, M. V. Perini, et al., “Liver Regeneration and Liver Metastasis,” Seminars in Cancer Biology 71, (2021): 86–97.

[323] Y. Takamizawa, M. Inoue, K. Moritani, et al., “Prognostic Impact of Conversion Hepatectomy for Initially Unresectable Colorectal Liver Metastasis,” Langenbecks Archives of Surgery 407, no. 7 (2022): 2893–2903.

[324] T. Arigami, D. Matsushita, K. Okubo, et al., “Indication and Prognostic Significance of Conversion Surgery in Patients With Liver Metastasis From Gastric Cancer,” Oncology 98, no. 5 (2020): 273–279.

[325] T. Ruers, F. Van Coevorden, C. J. Punt, et al., “Local Treatment of Unresectable Colorectal Liver Metastases: Results of a Randomized Phase II Trial,” JNCI: Journal of the National Cancer Institute 109, no. 9 (2017): djx015.

[326] Y. Han, D. Yan, F. Xu, et al., “Radiofrequency Ablation versus Liver Resection for Colorectal Cancer Liver Metastasis: An Updated Systematic Review and Meta-analysis,” Chinese Medical Journal 129, no 24 (2016): 2983–2990.

[327] L. J. Wang, Z. Y. Zhang, X. L. Yan, et al., “Radiofrequency Ablation versus Resection for Technically Resectable Colorectal Liver Metastasis: A Propensity Score Analysis,” World Journal of Surgical Oncology 16, no. 1 (2018): 207.

[328] F. Izzo, V. Granata, R. Grassi, et al., “Radiofrequency Ablation and Microwave Ablation in Liver Tumors: An Update,” Oncologist 24, no. 10 (2019): e990–e1005.

[329] P. Tinguely, S. J. S. Ruiter, J. Engstrand, et al., “A Prospective Multicentre Trial on Survival After Microwave Ablation VErsus Resection for Resectable Colorectal Liver Metastases (MAVERRIC),” European Journal of Cancer 187 (2023): 65–76.

[330] J. M. Roodhart, L. G. Daenen, E. C. Stigter, et al., “Mesenchymal Stem Cells Induce Resistance to Chemotherapy Through the Release of Platinum-induced Fatty Acids,” Cancer Cell 20, no. 3 (2011): 370–383.

[331] C. A. Wills, X. Liu, L. Chen, et al., “Chemotherapy-Induced Upregulation of Small Extracellular Vesicle-Associated PTX3 Accelerates Breast Cancer Metastasis,” Cancer Research 81, no. 2 (2021): 452–463.

[332] P. T. Huong, L. T. Nguyen, X. B. Nguyen, S. Kook Lee, D.-H. Bach, “The Role of Platelets in the Tumor-Microenvironment and the Drug Resistance of Cancer Cells,” Cancers (Basel) 11, no. (2) (2019): 240.

[333] L. G. Daenen, J. M. Roodhart, M. van Amersfoort, et al., “Chemotherapy Enhances Metastasis Formation via VEGFR-1-expressing Endothelial Cells,” Cancer Research 71, no. 22 (2011): 6976–6985.

[334] X. Wu, Q. Wu, X. Zhou, et al., “SphK1 functions Downstream of IGF-1 to Modulate IGF-1-induced EMT, Migration and Paclitaxel Resistance of A549 Cells: A Preliminary in Vitro Study,” Journal of Cancer 10, no. 18 (2019): 4264–4269.

[335] A. Barry, A. McPartlin, P. Lindsay, et al., “Dosimetric Analysis of Liver Toxicity After Liver Metastasis Stereotactic Body Radiation Therapy,” Practical Radiation Oncology 7, no. 5 (2017): e331–e337.

[336] A. Mahadevan, O. Blanck, R. Lanciano, et al., “Stereotactic Body Radiotherapy (SBRT) for Liver Metastasis—clinical Outcomes From the International Multi-institutional RSSearch® Patient Registry,” Radiation Oncology 13, no. 1 (2018): 26.

[337] J. Welsh, H. Menon, D. Chen, et al., “Pembrolizumab With or Without Radiation Therapy for Metastatic Non-small Cell Lung Cancer: A Randomized Phase I/II Trial,” Journal for ImmunoTherapy of Cancer 8, no. 2 (2020).

[338] E. Nolan, V. L. Bridgeman, L. Ombrato, et al., “Radiation Exposure Elicits a Neutrophil-driven Response in Healthy Lung Tissue That Enhances Metastatic Colonization,” Nature Cancer 3, no. 2 (2022): 173–187.

[339] F. Loupakis, C. Cremolini, G. Masi, et al., “Initial Therapy With FOLFOXIRI and bevacizumab for Metastatic Colorectal Cancer,” New England Journal of Medicine 371, no. 17 (2014): 1609–1618.

[340] E. Van Cutsem, C. H. Köhne, E. Hitre, et al., “Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer,” New England Journal of Medicine 360, no. 14 (2009): 1408–1417.

[341] C. Eng, T. W. Kim, J. Bendell, et al., “Atezolizumab With or Without Cobimetinib versus Regorafenib in Previously Treated Metastatic Colorectal Cancer (IMblaze370): A Multicentre, Open-label, Phase 3, Randomised, Controlled Trial,” Lancet Oncology 20, no. 6 (2019): 849–861.

[342] H. Jiang, D. Yu, P. Yang, et al., “Revealing the Transcriptional Heterogeneity of Organ-specific Metastasis in human Gastric Cancer Using Single-cell RNA Sequencing,” Clinical and Translational Medicine 12, no. 2 (2022): e730.

[343] Y. Liu, Q. Zhang, B. Xing, et al., “Immune Phenotypic Linkage Between Colorectal Cancer and Liver Metastasis,” Cancer Cell 40, no. 4 (2022): 424–437.

[344] I. N Crispe, “Hepatic T Cells and Liver Tolerance,” Nature Reviews Immunology 3, no. 1 (2003): 51–62.

[345] J. C. Lee, M. D. Green, L. A. Huppert, et al., “The Liver-Immunity Nexus and Cancer Immunotherapy,” Clinical Cancer Research 28, no. 1 (2022): 5–12.

[346] X. Ficht and M. Iannacone, “Immune Surveillance of the Liver by T Cells,” Science Immunology 5, no. 51 (2020).

[347] C. W. Steele, S. A. Karim, J. D. G. Leach, et al., “CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma,” Cancer Cell 2016; 29(6): 832–845.

[348] M. A. Socinski, R. M. Jotte, F. Cappuzzo, et al., “Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC,” New England Journal of Medicine 378, no. 24 (2018): 2288–2301.

[349] N. B. Mettu, F. S. Ou, T. J. Zemla, et al., “Assessment of Capecitabine and Bevacizumab With or without Atezolizumab for the Treatment of Refractory Metastatic Colorectal Cancer: A Randomized Clinical Trial,” JAMA Network Open 5, no. 2 (2022): e2149040.

[350] D. T. Le, J. N. Durham, K. N. Smith, et al., “Mismatch Repair Deficiency Predicts Response of Solid Tumors to PD-1 Blockade,” Science 357, no. 6349 (2017): 409–413.

[351] M. D. Hellmann, T. E. Ciuleanu, A. Pluzanski, et al., “Nivolumab plus Ipilimumab in Lung Cancer With a High Tumor Mutational Burden,” New England Journal of Medicine 378, no. 22 (2018): 2093–2104.

[352] J. M. Michot, C. Bigenwald, S. Champiat, et al., “Immune-related Adverse Events With Immune Checkpoint Blockade: A Comprehensive Review,” European Journal of Cancer 54 (2016): 139–148.

[353] A. D. Waldman, J. M. Fritz, and M. J Lenardo, “A Guide to Cancer Immunotherapy: From T Cell Basic Science to Clinical Practice,” Nature Reviews Immunology 20, no. 11 (2020): 651–668.

[354] G. L. Beatty, M. H. O’Hara, and S. F. Lacey, et al., “Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells against Pancreatic Carcinoma Metastases in a Phase 1 Trial,” Gastroenterology 155, no. 1 (2018): 29–32.

[355] M. Parkhurst, S. L. Goff, F. J. Lowery, et al., “Adoptive Transfer of Personalized Neoantigen-reactive TCR-transduced T Cells in Metastatic Colorectal Cancer: Phase 2 Trial Interim Results,” Nature Medicine 30, no. 9 (2024): 2586–2595.

[356] R. Leidner, N. Sanjuan Silva, H. Huang, et al., “Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer,” New England Journal of Medicine 386, no. 22 (2022): 2112–2119.

[357] M. E. Dudley, C. A. Gross, M. M. Langhan, et al., “CD8+ enriched “Young” Tumor Infiltrating Lymphocytes Can Mediate Regression of Metastatic Melanoma,” Clinical Cancer Research 16, no. 24 (2010): 6122–6131.

[358] Y. Quan, J. He, Q. Zou, et al., “Low Molecular Weight Heparin Synergistically Enhances the Efficacy of Adoptive and Anti-PD-1-based Immunotherapy by Increasing Lymphocyte Infiltration in Colorectal Cancer,” Journal for Immunotherapy of Cancer 11, no. 8 (2023).

[359] K. M. Maalej, M. Merhi, V. P. Inchakalody, et al., “CAR-Cell Therapy in the Era of Solid Tumor Treatment: Current Challenges and Emerging Therapeutic Advances,” Molecular Cancer 22, no. 1 (2023): 20.

[360] M. Peng, Y. Mo, Y. Wang, et al., “Neoantigen Vaccine: An Emerging Tumor Immunotherapy,” Molecular Cancer 18, no. 1 (2019): 128.

[361] T. Zhang, Z. Tai, F. Miao, et al., “Adoptive Cell Therapy for Solid Tumors Beyond CAR-T: Current Challenges and Emerging Therapeutic Advances,” The Journal of Controlled Release 368 (2024): 372–396.

[362] B. Wu, B. Zhang, B. Li, et al., “Cold and Hot Tumors: From Molecular Mechanisms to Targeted Therapy,” Signal Transduction Target Therapy 9, no. 1: 274.

[363] C. Xia, W. Bai, T. Deng, et al., “Sponge-Like Nano-system Suppresses Tumor Recurrence and Metastasis by Restraining Myeloid-derived Suppressor Cells-mediated Immunosuppression and Formation of Pre-metastatic Niche,” Acta Biomaterialia 158 (2023): 708–724.

[364] H. Tang, L. Leung, G. Saturno, et al., “Lysyl Oxidase Drives Tumour Progression by Trapping EGF Receptors at the Cell Surface,” Nature Communications 8 (2017): 14909.

[365] J. Liu, B. Jiang, W. Xu, et al., “Targeted Inhibition of CHKα and mTOR in Models of Pancreatic Ductal Adenocarcinoma: A Novel Regimen for Metastasis,” Cancer Letters 605 (2024): 217280.

[366] C. Donato, L. Kunz, F. Castro-Giner, et al., “Hypoxia Triggers the Intravasation of Clustered Circulating Tumor Cells,” Cell Reports 32, no. 10 (2020): 108105.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.