{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T01:20:37Z","timestamp":1792718437772,"version":"4.5.0"},"reference-count":136,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T00:00:00Z","timestamp":1623974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rather than primary solid tumors, metastasis is one of the hallmarks of most cancer deaths. Metastasis is a multistage event in which cancer cells escape from the primary tumor survive in the circulation and disseminate to distant sites. According to Stephen Paget\u2019s \u201cSeed and Soil\u201d hypothesis, metastatic capacity is determined not only by the internal oncogenic driving force but also by the external environment of tumor cells. Throughout the body, macrophages are required for maintaining tissue homeostasis, even in the tumor milieu. To fulfill these multiple functions, macrophages are polarized from the inflammation status (M1-like) to anti-inflammation status (M2-like) to maintain the balance between inflammation and regeneration. However, tumor cell-enforced tumor-associated macrophages (TAMs) (a high M2\/M1 ratio status) are associated with poor prognosis for most solid tumors, such as ovarian cancer. In fact, clinical evidence has verified that TAMs, representing up to 50% of the tumor mass, exert both protumor and immunosuppressive effects in promoting tumor metastasis through secretion of interleukin 10 (IL10), transforming growth factor \u03b2 (TGF\u03b2), and VEGF, expression of PD-1 and consumption of arginine to inhibit T cell anti-tumor function. However, the underlying molecular mechanisms by which the tumor microenvironment favors reprogramming of macrophages to TAMs to establish a premetastatic niche remain controversial. In this review, we examine the latest investigations of TAMs during tumor development, the microenvironmental factors involved in macrophage polarization, and the mechanisms of TAM-mediated tumor metastasis. We hope to dissect the critical roles of TAMs in tumor metastasis, and the potential applications of TAM-targeted therapeutic strategies in cancer treatment are discussed.<\/jats:p>","DOI":"10.3390\/ijms22126560","type":"journal-article","created":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T11:19:20Z","timestamp":1624015160000},"page":"6560","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":233,"title":["The Impact of the Tumor Microenvironment on Macrophage Polarization in Cancer Metastatic Progression"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8127-7842","authenticated-orcid":false,"given":"Huogang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Obstetrics & Gynaecology, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingo M. H.","family":"Yung","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynaecology, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hextan Y. S.","family":"Ngan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynaecology, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen K. L.","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynaecology, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynaecology, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1615\/CritRevOncog.v18.i1-2.40","article-title":"On the origin of cancer metastasis","volume":"18","author":"Seyfried","year":"2013","journal-title":"Crit. Rev. Oncog."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Loret, N., Denys, H., Tummers, P., and Berx, G. (2019). The role of epithelial-to-mesenchymal plasticity in ovarian cancer progression and therapy resistance. Cancers, 11.","DOI":"10.3390\/cancers11060838"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"8687","DOI":"10.2147\/OTT.S216355","article-title":"Tumor-associated macrophages (TAMs): A critical activator in ovarian cancer metastasis","volume":"12","author":"Yin","year":"2019","journal-title":"Onco. Targets Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41392-020-0134-x","article-title":"Molecular principles of metastasis: A hall mark of cancer revisited","volume":"5","author":"Fares","year":"2020","journal-title":"Signal. Transduct. Target Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"256","DOI":"10.3389\/fonc.2013.00256","article-title":"Getting to know ovarian cancer ascites: Opportunities for targeted therapy-based translational research","volume":"3","author":"Ahmed","year":"2013","journal-title":"Front. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s40425-017-0283-9","article-title":"The immune system in cancer metastasis: Friend or foe?","volume":"5","author":"Janssen","year":"2017","journal-title":"J. Immunother. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/nri3789","article-title":"Immune cell promotion of metastasis","volume":"15","author":"Kitamura","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1126\/science.aav0173","article-title":"Tumor metastasis to lymphnodes requiresYAP-dependent metabolic adaptation","volume":"363","author":"Lee","year":"2019","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1038\/s41423-020-0488-6","article-title":"The history and advances in cancer immunotherapy: Understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications","volume":"17","author":"Zhang","year":"2020","journal-title":"Cell. Mol. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1101\/gad.314617.118","article-title":"Roles of the immune system in cancer: From tumor initiation to metastatic progression","volume":"32","author":"Gonzalez","year":"2018","journal-title":"Genes Dev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.3389\/fimmu.2018.01364","article-title":"transforminggrowth factor-beta and inter leukin-10 synergistically regulate humoral immunity via modulating metabolic signals","volume":"9","author":"Komai","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"422","DOI":"10.4049\/jimmunol.1701019","article-title":"Myeloid-derived suppressor cells: Immune-suppressive cells that impair antitumor immunity and are sculpted by their environment","volume":"200","author":"Fenselau","year":"2018","journal-title":"J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1097\/PAP.0000000000000161","article-title":"Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International immuno-oncology biomarkers working group: Part 2: TILsin melanoma, gastrointestinal tract carcinomas, non-small cell lung carcinoma and mesothelioma, endometrial and ovarian carcinomas, squamous cell carcinoma of the head and neck, genitourinary carcinomas, and primary brain tumors","volume":"24","author":"Hendry","year":"2017","journal-title":"Adv. Anat. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1757-2215-7-19","article-title":"Ahigh M1\/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients","volume":"7","author":"Zhang","year":"2014","journal-title":"J. Ovarian. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"566511","DOI":"10.3389\/fonc.2020.566511","article-title":"Tumor-associated macrophages in human breast, colorectal, lung, ovarianand prostate cancers","volume":"10","author":"Larionova","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3678","DOI":"10.1073\/pnas.1817652116","article-title":"Infiltration of CD8(+) T cells in to tumor cell clusters in triple-negative breastcancer","volume":"116","author":"Li","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.immuni.2014.06.010","article-title":"Tumor-associated macrophages: From mechanisms to therapy","volume":"41","author":"Noy","year":"2014","journal-title":"Immunity"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1038\/s41467-018-02834-8","article-title":"The tumour micro environment create saniche for the self-renewal of tumour-promoting macrophages in colonadenoma","volume":"9","author":"Soncin","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.molmed.2018.03.006","article-title":"Macrophages: The road less traveled, changing anticancer therapy","volume":"24","author":"Guerriero","year":"2018","journal-title":"Trends Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s13045-019-0760-3","article-title":"Tumor-associated macrophages in tumor metastasis: Biological roles and clinical therapeutic applications","volume":"12","author":"Lin","year":"2019","journal-title":"J. Hematol. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.cell.2010.03.014","article-title":"Macrophage diversity enhances tumor progression and metastasis","volume":"141","author":"Qian","year":"2010","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.molcel.2019.10.023","article-title":"Cancer -derived succinate promotes macrophage polarization and cancer metastasis via succinate receptor","volume":"77","author":"Wu","year":"2020","journal-title":"Mol. Cell."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/j.cmet.2016.09.008","article-title":"Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis","volume":"24","author":"Wenes","year":"2016","journal-title":"Cell. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1158\/2159-8290.CD-20-0036","article-title":"Disabled homolog 2 controls prometastatic activity of tumor-associated macrophages","volume":"10","author":"Marigo","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1016\/j.ccell.2019.02.009","article-title":"Human tumor-associated macrophage and monocyte transcriptional landscapes reveal cancer-specific reprogramming, biomarkers, and therapeutic targets","volume":"35","author":"Cassetta","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"419","DOI":"10.3389\/fphys.2018.00419","article-title":"The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes","volume":"9","author":"Krzyszczyk","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/nature12034","article-title":"Macrophage biology in development, homeostasis and disease","volume":"496","author":"Wynn","year":"2013","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1016\/j.celrep.2018.10.047","article-title":"Analysis of single-cell RNA-Seq identifies cell-cell communication associated with tumor characteristics","volume":"25","author":"Kumar","year":"2018","journal-title":"Cell. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3928","DOI":"10.1038\/s41467-019-11788-4","article-title":"Macrophage spatial heterogeneity in gastric cancer defined by multiplex immunohisto chemistry","volume":"10","author":"Huang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"13","DOI":"10.12703\/P6-13","article-title":"The M1 and M2 paradigm of macrophage activation: Time for reassessment","volume":"6","author":"Martinez","year":"2014","journal-title":"F1000 Prime Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.3389\/fimmu.2019.01084","article-title":"Macrophage polarization: Different gene signatures in M1(LPS+) vs. classically and M2 (LPS-) vs. alternatively activated macrophages","volume":"10","author":"Orecchioni","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/nri2448","article-title":"Exploring the full spectrum of macrophage activation","volume":"8","author":"Mosser","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1111\/imcb.12236","article-title":"Macrophages in wound healing: Activation and plasticity","volume":"97","author":"Kim","year":"2019","journal-title":"Immunol. Cell. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1172\/JCI124615","article-title":"The role of macrophages in the resolution of inflammation","volume":"129","author":"Watanabe","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s41392-021-00484-9","article-title":"Targeting tumor-associated macrophages to synergize tumor immunotherapy","volume":"6","author":"Xiang","year":"2021","journal-title":"Signal. Transduct. Target Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1111\/pin.12440","article-title":"Role of tumor-associated macrophages in human malignancies: Friend or foe?","volume":"66","author":"Takeya","year":"2016","journal-title":"Pathol. Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.humpath.2008.08.011","article-title":"High tumor-infiltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection","volume":"40","author":"Ding","year":"2009","journal-title":"Hum. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3389\/fonc.2018.00049","article-title":"Targeting macrophages in cancer: From bench to bedside","volume":"8","author":"Poh","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1089\/thy.2011.0452","article-title":"Density of tumor-associated macrophages correlates with lymphno demetastasis in papillary thyroid carcinoma","volume":"22","author":"Qing","year":"2012","journal-title":"Thyroid"},{"key":"ref_40","first-page":"4490","article-title":"M2 tumor-associated macrophages promote tumor progression in non-small-cell lung cancer","volume":"18","author":"Sumitomo","year":"2019","journal-title":"Exp. Ther. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4160","DOI":"10.1158\/0008-5472.CAN-18-1691","article-title":"NOTCH signaling via WNT regulates the proliferation of alternative, CCR2-independent tumor-associated macrophages in hepatocellular carcinoma","volume":"79","author":"Ye","year":"2019","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"48436","DOI":"10.18632\/oncotarget.17061","article-title":"Redirecting tumor-associated macrophages to become tumoricidal effectors as a novel strategy for cancer therapy","volume":"8","author":"Zheng","year":"2017","journal-title":"Oncotarget"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1111\/imm.13196","article-title":"M2polarization of tumor-associated macrophages is dependent on integrin beta 3 via peroxi some proliferator-activated receptor-gamma up-regulation in breast cancer","volume":"160","author":"Shu","year":"2020","journal-title":"Immunology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"eaaz6105","DOI":"10.1126\/sciadv.aaz6105","article-title":"Reprogramming of tumor-associated macrophages by targeting beta-catenin\/FOSL2\/ARID5A signaling: A potentialtreatment of lung cancer","volume":"6","author":"Sarode","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_45","first-page":"4107","article-title":"Tumor associated macrophages in lung cancer: Friend or foe? (Review)","volume":"22","author":"Xu","year":"2020","journal-title":"Mol. Med. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.cmet.2019.06.001","article-title":"Macrophages and metabolism in the tumor microenvironment","volume":"30","author":"Vitale","year":"2019","journal-title":"Cell. Metab."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"324","DOI":"10.3389\/fonc.2020.00324","article-title":"Macrophage and tumor cell cross-talk is fundamental for lung tumor progression: We need to talk","volume":"10","author":"Sarode","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/s12929-019-0568-z","article-title":"Tumor-associated macrophages: Anaccomplice in solid tumor progression","volume":"26","author":"Chen","year":"2019","journal-title":"J. Biomed. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/s41392-020-0205-z","article-title":"Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies","volume":"5","year":"2020","journal-title":"Signal. Transduct. Target Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"899","DOI":"10.3389\/fonc.2020.00899","article-title":"The role of tumor-associated myeloid cells in modulating cancer therapy","volume":"10","author":"Neophytou","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"56408","DOI":"10.18632\/oncotarget.10895","article-title":"Inhibition of the colony-stimulating-factor-1receptor affects the resistance of lung cancer cells tocisplatin","volume":"7","author":"Pass","year":"2016","journal-title":"Oncotarget"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1038\/nrd.2018.169","article-title":"Targeting macrophages: Therapeutic approaches in cancer","volume":"17","author":"Cassetta","year":"2018","journal-title":"Nat. Rev. Drug. Discov."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1158\/0008-5472.CAN-09-1474","article-title":"A nets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis","volume":"70","author":"Zabuawala","year":"2010","journal-title":"Cancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s12943-019-0976-4","article-title":"Cross talk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis","volume":"18","author":"Wei","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.7150\/thno.51777","article-title":"Metabolic regulatory cross talk between tumor micro environment and tumor-associated macrophages","volume":"11","author":"Chen","year":"2021","journal-title":"Theranostics"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4709","DOI":"10.1002\/cam4.2327","article-title":"Crosstalk between cancer and immune cells: Role of tumor-associated macrophages in the tumor microenvironment","volume":"8","author":"Wang","year":"2019","journal-title":"Cancer Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.cell.2010.01.025","article-title":"Immunity, inflammation, and cancer","volume":"140","author":"Grivennikov","year":"2010","journal-title":"Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1038\/s41392-020-00449-4","article-title":"Advantages of targeting the tumor immune microenvironment over blocking immune checkpoint in cancer immunotherapy","volume":"6","author":"Tang","year":"2021","journal-title":"Signal. Transduct. Target Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2563","DOI":"10.1016\/j.bbamcr.2014.05.014","article-title":"Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease","volume":"1843","author":"Turner","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/nrc2734","article-title":"STAT sincancer inflammation and immunity: A leading role for STAT3","volume":"9","author":"Yu","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/s42003-019-0508-1","article-title":"Targeting of lipid metabolism with a metabolic inhibitor cocktaile radicates peritoneal metastases in ovarian cancer cells","volume":"2","author":"Chen","year":"2019","journal-title":"Commun. Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.21037\/atm-20-2037","article-title":"Metabolic reprograming of tumor-associated macrophages","volume":"8","author":"Puthenveetil","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/cr.2017.155","article-title":"Mitochondrial metabolism and cancer","volume":"28","author":"Porporato","year":"2018","journal-title":"Cell Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.yexcr.2017.03.043","article-title":"Macrophage heterogeneity and energy metabolism","volume":"360","author":"Verdeguer","year":"2017","journal-title":"Exp. Cell Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.3389\/fimmu.2019.01462","article-title":"The metabolic signature of macrophage responses","volume":"10","author":"Viola","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"532","DOI":"10.3389\/fimmu.2014.00532","article-title":"Metabolism via arginase or nitric oxide synthase: Two competing arginine pathways in macrophages","volume":"5","author":"Rath","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1158\/2326-6066.CIR-16-0259","article-title":"All-trans retinoic acid prevents osteosarcoma metastasis by inhibiting M2 polarization of tumor-associated macrophages","volume":"5","author":"Zhou","year":"2017","journal-title":"Cancer Immunol. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2394","DOI":"10.1084\/jem.20182124","article-title":"Specific targeting of CD163 (+) TAMs mobilizes inflammatory monocytes and promotes Tcell-mediated tumor regression","volume":"216","author":"Etzerodt","year":"2019","journal-title":"J. Exp. Med."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Poznanski, S.M., Singh, K., Ritchie, T.M., Aguiar, J.A., Fan, I.Y., Portillo, A.L., Rojas, E.A., Vahedi, F., El-Sayes, A., and Xing, S. (2021). Metabolic flexibility determines human NKcell functional fate in the tumor microenvironment. Cell Metab.","DOI":"10.1016\/j.cmet.2021.03.023"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/s41419-021-03781-x","article-title":"Sodium\/glucoseco transporter 1-dependent metabolic alterations induce tamoxifen resistance in breast cancer by promoting macrophage M2 polarization","volume":"12","author":"Niu","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1158\/0008-5472.CAN-19-2994","article-title":"Enhanced lipid accumulation and metabolism are required for the differentiation and activation of tumor-associated macrophages","volume":"80","author":"Su","year":"2020","journal-title":"Cancer Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1016\/j.cmet.2019.02.016","article-title":"Membrane cholesterol efflux drives tumor-associated macrophage reprogramming and tumor progression","volume":"29","author":"Goossens","year":"2019","journal-title":"Cell Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1038\/s41419-020-03189-z","article-title":"Exosomes and breast cancer drug resistance","volume":"11","author":"Dong","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"377","DOI":"10.3892\/ol.2021.12638","article-title":"Role of exosomes in the immune microenvironment of ovarian cancer","volume":"21","author":"Li","year":"2021","journal-title":"Oncol. Lett."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41389-019-0126-2","article-title":"Tumor-derived exosomal HMGB1 promotes esophageal squamous cell carcinoma progression through inducing PD1 (+) TAM expansion","volume":"8","author":"Li","year":"2019","journal-title":"Oncogenesis"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41419-018-0465-5","article-title":"Tumor-associated macrophages-derived exosomes promote the migration of gastric cancer cells by transfer of functional Apolipoprotein, E","volume":"9","author":"Zheng","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s12951-018-0403-9","article-title":"Recent advancements in the use of exosomes as drug delivery systems","volume":"16","author":"Bunggulawa","year":"2018","journal-title":"J. Nanobiotechnology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1016\/j.ymthe.2020.06.003","article-title":"Exosomes: A potential therapeutic tool targeting communications between tumorcells and macrophages","volume":"28","author":"Guo","year":"2020","journal-title":"Mol. Ther."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.omtn.2020.06.008","article-title":"Emerging function and clinical significance of exosomalcirc RNAs in cancer","volume":"21","author":"Wang","year":"2020","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2803","DOI":"10.2147\/IJN.S284560","article-title":"Down regulation of hsa_circ_0074854 suppresses the migration and invasion in hepatocellular carcinomavia interacting with Hu Rand via suppressing exosomes-mediated macrophage M2 polarization","volume":"16","author":"Wang","year":"2021","journal-title":"Int. J. Nanomedicine"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"522","DOI":"10.3892\/or.2017.5697","article-title":"Exosomes derived from hypoxicepithelial ovarian cancer deliver microRNA-940 to induce macrophage M2 polarization","volume":"38","author":"Chen","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"43076","DOI":"10.18632\/oncotarget.9246","article-title":"Epithelial ovarian cancer-secreted exosomal miR-222-3p induces polarization of tumor-associated macrophages","volume":"7","author":"Ying","year":"2016","journal-title":"Oncotarget"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1601479","DOI":"10.1080\/2162402X.2019.1601479","article-title":"SALL4-mediated up regulation of exosomal miR-146a-5p drives T-cell exhaustion b yM2tumor-associated macrophages in HCC","volume":"8","author":"Yin","year":"2019","journal-title":"Oncoimmunology"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"447","DOI":"10.3389\/fcell.2020.00447","article-title":"The multifaceted roles of MSCs in the tumor microenvironment: Interactions with immune cells and exploitation for therapy","volume":"8","author":"Papait","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"571516","DOI":"10.3389\/fonc.2020.571516","article-title":"Crosstalk between mesenchymal stromal cells and tumor-associated macrophages in gastric cancer","volume":"10","author":"Zheng","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3389\/fcell.2018.00018","article-title":"Exosome-Based Cell-Cell Communication in the Tumor Microenvironment","volume":"6","author":"Maia","year":"2018","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"6272498","DOI":"10.1155\/2020\/6272498","article-title":"Tumor-derived exosomes in immunosuppression and immunotherapy","volume":"2020","author":"Olejarz","year":"2020","journal-title":"J. Immunol. Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1158\/0008-5472.CAN-20-2990","article-title":"macrophage-based approaches for cancer immunotherapy","volume":"81","author":"Anderson","year":"2021","journal-title":"Cancer Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature01322","article-title":"Inflammation and cancer","volume":"420","author":"Coussens","year":"2002","journal-title":"Nature"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1038\/nm.3394","article-title":"Microenvironmental regulation of tumor progression and metastasis","volume":"19","author":"Quail","year":"2013","journal-title":"Nat. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.trecan.2020.02.022","article-title":"Turning cold into hot: Firing up the tumor microenvironment","volume":"6","author":"Duan","year":"2020","journal-title":"Trends Cancer"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"4557","DOI":"10.1158\/0008-5472.CAN-18-3962","article-title":"The tumor microenvironment innately modulates cancer progression","volume":"79","author":"Hinshaw","year":"2019","journal-title":"Cancer Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1007\/s10555-016-9643-z","article-title":"One microenvironment does not fit all: Heterogeneity beyond cancer cells","volume":"35","author":"Kim","year":"2016","journal-title":"Cancer Metastasis Rev."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"56","DOI":"10.3389\/fcell.2018.00056","article-title":"Underlying causes and therapeutic targeting of the inflammatory tumor microenvironment","volume":"6","author":"Comen","year":"2018","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"3221","DOI":"10.1158\/0008-5472.CAN-08-2871","article-title":"The EGF\/CSF-1paracrine invasion loop can be triggered by heregulin beta1 and CXCL12","volume":"69","author":"Hernandez","year":"2009","journal-title":"Cancer Res"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.cell.2010.03.015","article-title":"Matrix metal loproteinases: Regulators of the tumor microenvironment","volume":"141","author":"Kessenbrock","year":"2010","journal-title":"Cell"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ccell.2016.05.017","article-title":"The multifaceted role of perivascular macrophagesin tumors","volume":"30","author":"Lewis","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.gendis.2018.05.001","article-title":"Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis","volume":"5","author":"Feng","year":"2018","journal-title":"Genes Dis."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"4157","DOI":"10.1172\/JCI87252","article-title":"Tumor-associated macrophages drive spheroid formation during early transcoelomic metastasis of ovarian cancer","volume":"126","author":"Yin","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1146\/annurev-cancerbio-050216-121919","article-title":"Stress-induced mutagenesis: Implications in cancer and drug resistance","volume":"1","author":"Fitzgerald","year":"2017","journal-title":"Annu. Rev. Cancer Biol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.molcel.2019.06.029","article-title":"Mutation rate heterogeneity increases odds of survival in unpredictable environments","volume":"75","author":"Matic","year":"2019","journal-title":"Mol. Cell"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"7828","DOI":"10.1126\/sciadv.aat7828","article-title":"Cell fusion potentialtes tumor heterogeneity and reveals circulating hybrid cells that correlate with stage and survival","volume":"4","author":"Gast","year":"2018","journal-title":"Sci. Adv."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Belgiovine, C., Digifico, E., Anfray, C., Ummarino, A., and TorresAndon, F. (2020). Targeting tumor-associated macrophages in anti-cancer therapies: Convincing the traitors to do the right thing. J. Clin. Med., 9.","DOI":"10.3390\/jcm9103226"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"847","DOI":"10.3389\/fimmu.2018.00847","article-title":"Interferon-gamma at the crossroads of tumor immune surveillance or evasion","volume":"9","author":"Castro","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"101174","DOI":"10.1016\/j.redox.2019.101174","article-title":"Targeting immune cells for cancer therapy","volume":"25","author":"Gun","year":"2019","journal-title":"Redox Biol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.ccell.2016.08.004","article-title":"T cell cancer therapy requires CD40-CD40L activation of tumor necrosis factor and inducible nitric-oxide-synthase-producing dendritic cells","volume":"30","author":"Marigo","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"E4041","DOI":"10.1073\/pnas.1720948115","article-title":"Macrophages impede CD8T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment","volume":"115","author":"Peranzoni","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Anfray, C., Ummarino, A., Andon, F.T., and Allavena, P. (2019). Current strategies to target tumor-associated-macrophages to improve anti-tumor immune responses. Cells, 9.","DOI":"10.3390\/cells9010046"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2629","DOI":"10.3389\/fimmu.2018.02629","article-title":"Targeting macrophage-recruiting chemokines as a novel therapeutic strategy to prevent the progression of solid tumors","volume":"9","author":"Argyle","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"3026","DOI":"10.2174\/0929867324666170830111531","article-title":"TargetingCXCL12\/CXCR4Axis in tumor immunotherapy","volume":"26","author":"Zhou","year":"2019","journal-title":"Curr. Med. Chem."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.yexcr.2019.03.013","article-title":"CXCL12\/CXCR4 path way orchestrates CSC-like properties by CAF recruited tumor associated macrophage in OSCC","volume":"378","author":"Li","year":"2019","journal-title":"Exp. Cell Res."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1111\/his.12407","article-title":"High intra tumor almacrophage content is an adverse prognostic feature in anaplastic large cell lymphoma","volume":"65","author":"Pedersen","year":"2014","journal-title":"Histopathology"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/icb.2011.58","article-title":"Control of macrophage lineage populations by CSF-1 receptor and GM-CSF in homeostasis and inflammation","volume":"90","author":"Lenzo","year":"2012","journal-title":"Immunol. Cell Biol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/s40425-017-0257-y","article-title":"Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy","volume":"5","author":"Cannarile","year":"2017","journal-title":"J. Immunother. Cancer"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.2147\/DDDT.S253232","article-title":"Pexidartinib, a novel small molecule CSF-1R inhibitor in use for tenosynovial giant cell tumor: A systematic review of pre-clinical and clinical development","volume":"14","author":"Benner","year":"2020","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.neo.2019.05.006","article-title":"Clodronate-liposome mediated macrophage depletion abrogates multiple myeloma tumor establishment in vivo","volume":"21","author":"Opperman","year":"2019","journal-title":"Neoplasia"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1186\/s12943-019-1102-3","article-title":"Harnessing tumor-associated macrophages as aids for cancer immunotherapy","volume":"18","author":"Li","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Rosowski, E.E. (2020). Determining macrophage versus neutrophil contributions to in nateimmunity using larval zebrafish. Dis. Model. Mech., 13.","DOI":"10.1242\/dmm.041889"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41467-021-21066-x","article-title":"High-through put phenotypic screen and transcriptional analysis identify new compound sand targets for macrophage reprogramming","volume":"12","author":"Hu","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1038\/s41587-020-0462-y","article-title":"Human chimeric antigenreceptor macrophages for cancer immunotherapy","volume":"38","author":"Klichinsky","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"eaaz6579","DOI":"10.1126\/sciadv.aaz6579","article-title":"Cellular backpacks for macrophage immunotherapy","volume":"6","author":"Shields","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"3974","DOI":"10.1038\/s41467-019-11911-5","article-title":"Genetic programming of macrophages to performanti-tumorfunctions using targeted mRNA nanocarriers","volume":"10","author":"Zhang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1038\/s41467-020-20723-x","article-title":"Boosting anti-PD-1 therapy with metformin-loaded macrophage-derived microparticles","volume":"12","author":"Wei","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"10692","DOI":"10.18632\/oncotarget.2530","article-title":"Potential therapeutic effect of the secretome from human uterine cervical stem cells against both cancer and stromal cells compared with a dipose tissue stem cells","volume":"5","author":"Eiro","year":"2014","journal-title":"Oncotarget"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"531","DOI":"10.3727\/096368916X693699","article-title":"Is immune modulation the mechanism underlying the beneficial effects of amniotic cells and their derivatives in regenerative medicine?","volume":"26","author":"Silini","year":"2017","journal-title":"Cell Transplant."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Cheng, N., Watkins-Schulz, R., Junkins, R.D., David, C.N., Johnson, B.M., Montgomery, S.A., Peine, K.J., Darr, D.B., Yuan, H., and McKinnon, K.P. (2018). Ananoparticle-incorporated STING activator enhances antitumorimmunity in PD-L1-insensitive models of triple-negative breast cancer. J. CI Insight, 3.","DOI":"10.1172\/jci.insight.120638"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/ni.3253","article-title":"Phagocytosis of a poptotic cells in homeostasis","volume":"16","author":"Arandjelovic","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1038\/s41568-019-0183-z","article-title":"Phagocytosis check points as new targets for cancer immunotherapy","volume":"19","author":"Feng","year":"2019","journal-title":"Nat. Rev. Cancer"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"496","DOI":"10.5483\/BMBRep.2017.50.10.147","article-title":"Dead cell phagocytosis and in nateimmune check point","volume":"50","author":"Yoon","year":"2017","journal-title":"BMB Rep."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3389\/fimmu.2020.00018","article-title":"Advances in anti-tumor treatments targeting the CD47\/SIR palpha axis","volume":"11","author":"Zhang","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/s41586-019-1456-0","article-title":"CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy","volume":"572","author":"Barkal","year":"2019","journal-title":"Nature"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"105514","DOI":"10.1016\/j.phrs.2021.105514","article-title":"Intrinsic strategies for the evasion of cGAS-STING signaling -mediated immune surveillance in human cancer: How therapy can overcome them","volume":"166","author":"Zou","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/s41580-020-0244-x","article-title":"Molecular mechanism sand cellular functions of cGAS-STING signalling","volume":"21","author":"Hopfner","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"498","DOI":"10.7150\/thno.37745","article-title":"Targeting the STING pathway in tumor-associated macrophages regulates in nateimmune sensing of gastric cancer cells","volume":"10","author":"Miao","year":"2020","journal-title":"Theranostics"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1038\/s41422-020-00395-4","article-title":"Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy","volume":"30","author":"Lv","year":"2020","journal-title":"Cell Res."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/nature25432","article-title":"Chromosomal instability drives metastasis through acytosolic DNA response","volume":"553","author":"Bakhoum","year":"2018","journal-title":"Nature"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/12\/6560\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:18:32Z","timestamp":1760163512000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/12\/6560"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,18]]},"references-count":136,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22126560"],"URL":"https:\/\/doi.org\/10.3390\/ijms22126560","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,18]]}}}