{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T14:58:56Z","timestamp":1791644336834,"version":"4.3.4"},"reference-count":106,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["24-15-00356"],"award-info":[{"award-number":["24-15-00356"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"award":["24-15-00356"],"award-info":[{"award-number":["24-15-00356"]}],"id":[{"id":"https:\/\/ror.org\/03y2gwe85","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Tumor-associated macrophages (TAMs) are considered to be one of the most attractive targets in cancer therapy but attempts to target them have produced variable and often contradictory results. Their phenotype and function are shaped by developmental origin, spatial niche, metabolic conditions, immune context, and treatment history. For this reason, TAM-directed therapy should not be approached as a simple problem of depletion or repolarization, but as a problem of function and timing. This framework integrates converging evidence from multiple independently reported studies of stage-, sequence-, and context-dependent macrophage targeting into a single decision structure, rather than proposing a new biological mechanism. We discuss here recurrent macrophage functions in solid tumors, including vascular support, matrix remodeling, immune exclusion, tumor-cell survival, antigen presentation, and tissue repair after therapy. We then consider how these functions affect the choice between depletion, recruitment blockade, reprogramming, and activation, and why the same intervention may be beneficial, ineffective, or harmful depending on lesion state and treatment sequence. Particular attention is given to therapeutic windows, biomarker-guided personalization, and adverse consequences of TAM intervention, including toxicity, compensatory myeloid substitution, loss of protective immune functions, repair-driven relapse, and the selection of inflammation-adapted or macrophage-resistant tumor cells. Effective TAM therapy will require functional precision, temporal precision, dynamic reassessment, and explicit attention to macrophage plasticity as both an opportunity and a source of risk.<\/jats:p>","DOI":"10.3390\/ijms27156916","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:57:56Z","timestamp":1785761876000},"page":"6916","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Macrophage Plasticity in Cancer Therapy: Function, Timing, and Tradeoffs"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6132-9924","authenticated-orcid":false,"given":"Olga","family":"Kovaleva","sequence":"first","affiliation":[{"name":"Institute of Experimental Oncology and Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Moscow 115478, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2137-1866","authenticated-orcid":false,"given":"Alexei","family":"Gratchev","sequence":"additional","affiliation":[{"name":"Institute of Experimental Oncology and Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Moscow 115478, Russia"},{"name":"Center for Bio- and Medical Technologies, Skolkovo Institute of Science and Technology, Moscow 121205, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"5665","DOI":"10.1038\/s41467-024-49885-8","article-title":"Using a pan-cancer atlas to investigate tumour associated macrophages as regulators of immunotherapy response","volume":"15","author":"Coulton","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.cell.2021.01.010","article-title":"A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells","volume":"184","author":"Cheng","year":"2021","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1126\/science.ade2292","article-title":"CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers","volume":"381","author":"Bill","year":"2023","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/j.0300-9475.2005.01524.x","article-title":"Interleukin-4 and dexamethasone counterregulate extracellular matrix remodelling and phagocytosis in type-2 macrophages","volume":"61","author":"Gratchev","year":"2005","journal-title":"Scand. J. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6553","DOI":"10.4049\/jimmunol.180.10.6553","article-title":"Activation of a TGF-beta-specific multistep gene expression program in mature macrophages requires glucocorticoid-mediated surface expression of TGF-beta receptor II","volume":"180","author":"Gratchev","year":"2008","journal-title":"J. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/j.it.2023.10.007","article-title":"Tumor macrophage functional heterogeneity can inform the development of novel cancer therapies","volume":"44","author":"Nasir","year":"2023","journal-title":"Trends Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1158\/2159-8290.CD-15-0012","article-title":"Real-Time Imaging Reveals Local, Transient Vascular Permeability, and Tumor Cell Intravasation Stimulated by TIE2hi Macrophage\u2013Derived VEGFA","volume":"5","author":"Harney","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1038\/s41467-022-29366-6","article-title":"Single-cell and spatial analysis reveal interaction of FAP+ fibroblasts and SPP1+ macrophages in colorectal cancer","volume":"13","author":"Qi","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1016\/j.ccell.2021.10.008","article-title":"Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation","volume":"39","author":"Duraiswamy","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1158\/2326-6066.CIR-20-0968","article-title":"Chemotherapy Induces Tumor-Associated Macrophages that Aid Adaptive Immune Responses in Ovarian Cancer","volume":"9","author":"Heath","year":"2021","journal-title":"Cancer Immunol. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"eadd1834","DOI":"10.1126\/scitranslmed.add1834","article-title":"The CSF-1R inhibitor pexidartinib affects FLT3-dependent DC differentiation and may antagonize durvalumab effect in patients with advanced cancers","volume":"16","author":"Voissiere","year":"2024","journal-title":"Sci. Transl. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1038\/nrc2013","article-title":"Cancer as an evolutionary and ecological process","volume":"6","author":"Merlo","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1158\/0008-5472.CAN-05-4005","article-title":"Distinct role of macrophages in different tumor microenvironments","volume":"66","author":"Lewis","year":"2006","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"110865","DOI":"10.1016\/j.celrep.2022.110865","article-title":"Tumor-associated macrophage heterogeneity is driven by tissue territories in breast cancer","volume":"39","author":"Laviron","year":"2022","journal-title":"Cell Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1158\/2159-8290.CD-23-1300","article-title":"Spatially Segregated Macrophage Populations Predict Distinct Outcomes in Colon Cancer","volume":"14","author":"Matusiak","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.ccr.2005.08.002","article-title":"Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors","volume":"8","author":"Venneri","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1158\/0008-5472.CAN-13-1196","article-title":"Tumor Hypoxia Does Not Drive Differentiation of Tumor-Associated Macrophages but Rather Fine-Tunes the M2-like Macrophage Population","volume":"74","author":"Laoui","year":"2014","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/s41698-024-00660-4","article-title":"Tumor-associated macrophage clusters linked to immunotherapy in a pan-cancer census","volume":"8","author":"Wei","year":"2024","journal-title":"npj Precis. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1016\/j.cell.2022.02.021","article-title":"Tissue-resident FOLR2+ macrophages associate with CD8+ T cell infiltration in human breast cancer","volume":"185","author":"Bromley","year":"2022","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2536","DOI":"10.1084\/jem.20180534","article-title":"Macrophages of distinct origins contribute to tumor development in the lung","volume":"215","author":"Loyher","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/j.it.2022.04.008","article-title":"Macrophage diversity in cancer revisited in the era of single-cell omics","volume":"43","author":"Ma","year":"2022","journal-title":"Trends Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1186\/s13059-017-1362-4","article-title":"Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment","volume":"18","author":"Kohanbash","year":"2017","journal-title":"Genome Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"101584","DOI":"10.1016\/j.isci.2020.101584","article-title":"Interleukin-34 Limits the Therapeutic Effects of Immune Checkpoint Blockade","volume":"23","author":"Hama","year":"2020","journal-title":"iScience"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1158\/1078-0432.CCR-22-2041","article-title":"Colorectal Cancer Metastases in the Liver Establish Immunosuppressive Spatial Networking between Tumor-Associated SPP1+ Macrophages and Fibroblasts","volume":"29","author":"Sathe","year":"2023","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.jhep.2023.01.011","article-title":"Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy","volume":"78","author":"Liu","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"eabg9518","DOI":"10.1126\/sciadv.abg9518","article-title":"Macrophages orchestrate the expansion of a proangiogenic perivascular niche during cancer progression","volume":"7","author":"Opzoomer","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/nature13490","article-title":"Functional polarization of tumour-associated macrophages by tumour-derived lactic acid","volume":"513","author":"Colegio","year":"2014","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3291","DOI":"10.1158\/0008-5472.CAN-22-1427","article-title":"Lipid-Associated Macrophages Are Induced by Cancer-Associated Fibroblasts and Mediate Immune Suppression in Breast Cancer","volume":"82","author":"Timperi","year":"2022","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1038\/s43018-024-00775-4","article-title":"Tumor-associated macrophages restrict CD8+ T cell function through collagen deposition and metabolic reprogramming of the breast cancer microenvironment","volume":"5","author":"Tharp","year":"2024","journal-title":"Nat. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"E4041","DOI":"10.1073\/pnas.1720948115","article-title":"Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti\u2013PD-1 treatment","volume":"115","author":"Peranzoni","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"101420","DOI":"10.1016\/j.xcrm.2024.101420","article-title":"PD-L1-expressing tumor-associated macrophages are immunostimulatory and associate with good clinical outcome in human breast cancer","volume":"5","author":"Wang","year":"2024","journal-title":"Cell Rep. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1007\/s00262-021-02861-3","article-title":"Activity of tumor-associated macrophage depletion by CSF1R blockade is highly dependent on the tumor model and timing of treatment","volume":"70","author":"Orf","year":"2021","journal-title":"Cancer Immunol. Immunother. CII"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e120631","DOI":"10.1172\/jci.insight.120631","article-title":"Compensation between CSF1R+ macrophages and Foxp3+ Treg cells drives resistance to tumor immunotherapy","volume":"3","author":"Gyori","year":"2018","journal-title":"JCI Insight"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1136\/gutjnl-2017-313738","article-title":"Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma","volume":"67","author":"Nywening","year":"2018","journal-title":"Gut"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3479","DOI":"10.1158\/0008-5472.CAN-14-3587","article-title":"Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy","volume":"75","author":"Hughes","year":"2015","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.immuni.2017.07.014","article-title":"Tissue-Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from Embryonic Hematopoiesis and Promote Tumor Progression","volume":"47","author":"Zhu","year":"2017","journal-title":"Immunity"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1038\/nm.3337","article-title":"CSF-1R inhibition alters macrophage polarization and blocks glioma progression","volume":"19","author":"Pyonteck","year":"2013","journal-title":"Nat. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5057","DOI":"10.1158\/0008-5472.CAN-13-3723","article-title":"CSF1\/CSF1R Blockade Reprograms Tumor-Infiltrating Macrophages and Improves Response to T-cell Checkpoint Immunotherapy in Pancreatic Cancer Models","volume":"74","author":"Zhu","year":"2014","journal-title":"Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1093\/annonc\/mdz163","article-title":"Phase I study of emactuzumab single agent or in combination with paclitaxel in patients with advanced\/metastatic solid tumors reveals depletion of immunosuppressive M2-like macrophages","volume":"30","author":"Italiano","year":"2019","journal-title":"Ann. Oncol. Off. J. Eur. Soc. Med. Oncol.\/ESMO"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e001006","DOI":"10.1136\/jitc-2020-001006","article-title":"Safety and efficacy of AMG 820, an anti-colony-stimulating factor 1 receptor antibody, in combination with pembrolizumab in adults with advanced solid tumors","volume":"8","author":"Razak","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/S1470-2045(16)00078-4","article-title":"Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: A single-centre, open-label, dose-finding, non-randomised, phase 1b trial","volume":"17","author":"Nywening","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/nature20554","article-title":"Overcoming resistance to checkpoint blockade therapy by targeting PI3Kgamma in myeloid cells","volume":"539","author":"Rausch","year":"2016","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"eaau9240","DOI":"10.1126\/scitranslmed.aau9240","article-title":"Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies","volume":"11","author":"Panni","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.cell.2020.07.013","article-title":"TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy","volume":"182","author":"Molgora","year":"2020","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1158\/1078-0432.CCR-21-2160","article-title":"First-in-Class Anti-immunoglobulin\u2013like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors","volume":"28","author":"Siu","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"101307","DOI":"10.1016\/j.xcrm.2023.101307","article-title":"Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors: The phase I\/II first-in-human MATINS trial","volume":"4","author":"Rannikko","year":"2023","journal-title":"Cell Rep. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4574","DOI":"10.1158\/1078-0432.CCR-21-1047","article-title":"Neoadjuvant Selicrelumab, an Agonist CD40 Antibody, Induces Changes in the Tumor Microenvironment in Patients with Resectable Pancreatic Cancer","volume":"27","author":"Byrne","year":"2021","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/j.ccr.2013.11.007","article-title":"Impeding macrophage entry into hypoxic tumor areas by Sema3A\/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity","volume":"24","author":"Casazza","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e001153","DOI":"10.1136\/jitc-2020-001153","article-title":"Phase Ib study of anti-CSF-1R antibody emactuzumab in combination with CD40 agonist selicrelumab in advanced solid tumor patients","volume":"8","author":"Machiels","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1200\/JCO.2010.32.8971","article-title":"Randomized phase III trial of paclitaxel\/carboplatin with or without PF-3512676 (Toll-like receptor 9 agonist) as first-line treatment for advanced non-small-cell lung cancer","volume":"29","author":"Hirsh","year":"2011","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2998","DOI":"10.1158\/2159-8290.CD-21-0425","article-title":"Overcoming PD-1 Blockade Resistance with CpG-A Toll-Like Receptor 9 Agonist Vidutolimod in Patients with Metastatic Melanoma","volume":"11","author":"Ribas","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1158\/2159-8290.CD-18-0280","article-title":"SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase Ib, Multicenter Study","volume":"8","author":"Ribas","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1158\/1078-0432.CCR-22-2235","article-title":"Combination of the STING Agonist MIW815 (ADU-S100) and PD-1 Inhibitor Spartalizumab in Advanced\/Metastatic Solid Tumors or Lymphomas: An Open-Label, Multicenter, Phase Ib Study","volume":"29","author":"Sweis","year":"2023","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"179","DOI":"10.4049\/jimmunol.1600146","article-title":"CSF-1R-Dependent Lethal Hepatotoxicity When Agonistic CD40 Antibody Is Given before but Not after Chemotherapy","volume":"197","author":"Byrne","year":"2016","journal-title":"J. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1158\/2326-6066.CIR-14-0182","article-title":"Systemic Agonistic Anti-CD40 Treatment of Tumor-Bearing Mice Modulates Hepatic Myeloid-Suppressive Cells and Causes Immune-Mediated Liver Damage","volume":"3","author":"Ma","year":"2015","journal-title":"Cancer Immunol. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e146314","DOI":"10.1172\/jci.insight.146314","article-title":"TNF blockade uncouples toxicity from antitumor efficacy induced with CD40 chemoimmunotherapy","volume":"6","author":"Stone","year":"2021","journal-title":"JCI Insight"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1186\/s12943-023-01884-x","article-title":"A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better","volume":"22","author":"Djureinovic","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Tiwari, A., Oravecz, T., Dillon, L.A., Italiano, A., Audoly, L., Fridman, W.H., and Clifton, G.T. (2023). Towards a consensus definition of immune exclusion in cancer. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1084887"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e006773","DOI":"10.1136\/jitc-2023-006773","article-title":"Developing a definition of immune exclusion in cancer: Results of a modified Delphi workshop","volume":"11","author":"Clifton","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e009160","DOI":"10.1136\/jitc-2024-009160","article-title":"Eganelisib combined with immune checkpoint inhibitor therapy and chemotherapy in frontline metastatic triple-negative breast cancer triggers macrophage reprogramming, immune activation and extracellular matrix reorganization in the tumor microenvironment","volume":"12","author":"Hubbard","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"eabd4550","DOI":"10.1126\/scitranslmed.abd4550","article-title":"Macrophage depletion induces edema through release of matrix-degrading proteases and proteoglycan deposition","volume":"13","author":"Bissinger","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/S0140-6736(19)30764-0","article-title":"Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): A randomised phase 3 trial","volume":"394","author":"Tap","year":"2019","journal-title":"Lancet"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1007\/s10549-024-07555-9","article-title":"Pexidartinib and standard neoadjuvant therapy in the adaptively randomized I-SPY2 trial for early breast cancer","volume":"209","author":"Rugo","year":"2025","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1093\/neuonc\/nov245","article-title":"Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: An Ivy Foundation Early Phase Clinical Trials Consortium phase II study","volume":"18","author":"Butowski","year":"2016","journal-title":"Neuro-Oncology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.ccell.2024.04.002","article-title":"A temporal perspective for tumor-associated macrophage identities and functions","volume":"42","author":"Bleriot","year":"2024","journal-title":"Cancer Cell"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"eadk3981","DOI":"10.1126\/sciimmunol.adk3981","article-title":"Timing and location dictate monocyte fate and their transition to tumor-associated macrophages","volume":"9","author":"Dunsmore","year":"2024","journal-title":"Sci. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"31097","DOI":"10.18632\/oncotarget.8857","article-title":"Stabilin-1 is expressed in human breast cancer and supports tumor growth in mammary adenocarcinoma mouse model","volume":"7","author":"Riabov","year":"2016","journal-title":"Oncotarget"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"EMMM201809342","DOI":"10.15252\/emmm.201809342","article-title":"Radiation combined with macrophage depletion promotes adaptive immunity and potentiates checkpoint blockade","volume":"10","author":"Jones","year":"2018","journal-title":"EMBO Mol. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1093\/neuonc\/not149","article-title":"Blockade of SDF-1 after irradiation inhibits tumor recurrences of autochthonous brain tumors in rats","volume":"16","author":"Liu","year":"2014","journal-title":"Neuro-Oncology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1093\/neuonc\/nov272","article-title":"Colony stimulating factor 1 receptor inhibition delays recurrence of glioblastoma after radiation by altering myeloid cell recruitment and polarization","volume":"18","author":"Stafford","year":"2016","journal-title":"Neuro-Oncology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e1151595","DOI":"10.1080\/2162402X.2016.1151595","article-title":"Timing of CSF-1\/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy","volume":"5","author":"Holmgaard","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1016\/j.ccell.2024.04.011","article-title":"Immunotherapy-activated T cells recruit and skew late-stage activated M1-like macrophages that are critical for therapeutic efficacy","volume":"42","author":"Middelburg","year":"2024","journal-title":"Cancer Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e20240957","DOI":"10.1084\/jem.20240957","article-title":"Targeting CD206+ macrophages disrupts the establishment of a key antitumor immune axis","volume":"222","author":"Ray","year":"2025","journal-title":"J. Exp. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"eabd1616","DOI":"10.1126\/scitranslmed.abd1616","article-title":"Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models","volume":"13","author":"Kadioglu","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1053\/j.gastro.2016.02.070","article-title":"Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice","volume":"150","author":"Seifert","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e2409668121","DOI":"10.1073\/pnas.2409668121","article-title":"Imaging of tumor-associated macrophage dynamics during immunotherapy using a CD163-specific nanobody-based immunotracer","volume":"121","author":"Lauwers","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"101611","DOI":"10.1016\/j.xcrm.2024.101611","article-title":"Monitoring melanoma patients on treatment reveals a distinct macrophage population driving targeted therapy resistance","volume":"5","author":"Vasilevska","year":"2024","journal-title":"Cell Rep. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"5694","DOI":"10.1038\/s41467-024-49916-4","article-title":"Single-cell resolution characterization of myeloid-derived cell states with implication in cancer outcome","volume":"15","author":"Guimaraes","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s12943-023-01931-7","article-title":"Deciphering tumor microenvironment: CXCL9 and SPP1 as crucial determinants of tumor-associated macrophage polarity and prognostic indicators","volume":"23","author":"Su","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1016\/j.ccell.2024.11.005","article-title":"Chemotherapy induces myeloid-driven spatially confined T cell exhaustion in ovarian cancer","volume":"42","author":"Launonen","year":"2024","journal-title":"Cancer Cell"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1016\/j.ccell.2024.08.012","article-title":"Fibrotic response to anti-CSF-1R therapy potentiates glioblastoma recurrence","volume":"42","author":"Watson","year":"2024","journal-title":"Cancer Cell"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"e97792","DOI":"10.1172\/jci.insight.97792","article-title":"CSF1R-dependent myeloid cells are required for NK-mediated control of metastasis","volume":"3","author":"Beffinger","year":"2018","journal-title":"JCI Insight"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e1115177","DOI":"10.1080\/2162402X.2015.1115177","article-title":"G-CSF regulates macrophage phenotype and associates with poor overall survival in human triple-negative breast cancer","volume":"5","author":"Hollmen","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1158\/2326-6066.CIR-13-0190","article-title":"The promotion of breast cancer metastasis caused by inhibition of CSF-1R\/CSF-1 signaling is blocked by targeting the G-CSF receptor","volume":"2","author":"Swierczak","year":"2014","journal-title":"Cancer Immunol. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1172\/JCI44562","article-title":"TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice","volume":"121","author":"Welford","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"6828","DOI":"10.1158\/0008-5472.CAN-16-1114","article-title":"Tie2 Expression on Macrophages Is Required for Blood Vessel Reconstruction and Tumor Relapse after Chemotherapy","volume":"76","author":"Chen","year":"2016","journal-title":"Cancer Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1038\/nature13862","article-title":"Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis","volume":"515","author":"Bonapace","year":"2014","journal-title":"Nature"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/s41577-019-0127-6","article-title":"Macrophages as regulators of tumour immunity and immunotherapy","volume":"19","author":"DeNardo","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/s41573-022-00520-5","article-title":"Macrophages as tools and targets in cancer therapy","volume":"21","author":"Mantovani","year":"2022","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1758835919854238","DOI":"10.1177\/1758835919854238","article-title":"Phase Ib study of the combination of pexidartinib (PLX3397), a CSF-1R inhibitor, and paclitaxel in patients with advanced solid tumors","volume":"11","author":"Wesolowski","year":"2019","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1038\/s41467-023-37361-8","article-title":"Monocyte depletion enhances neutrophil influx and proneural to mesenchymal transition in glioblastoma","volume":"14","author":"Chen","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"eaal3604","DOI":"10.1126\/scitranslmed.aal3604","article-title":"In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy","volume":"9","author":"Arlauckas","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.ccell.2017.11.004","article-title":"Myeloid Cell-Derived Reactive Oxygen Species Induce Epithelial Mutagenesis","volume":"32","author":"Canli","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Kovaleva, O.V., Sinyov, V.V., Rashidova, M.A., Malashenko, O.S., Podlesnaya, P.A., Kopnin, P.B., Vasileva, M.V., Balkin, A.S., Plotnikov, A., and Gratchev, A. (2026). The M1 Paradox: Pro-Tumorigenic Effect of Macrophage Cytotoxicity in Prostate Cancer. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27083655"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Kovaleva, O.V., Rashidova, M.A., Sinyov, V.V., Malashenko, O.S., and Gratchev, A. (2025). M1 macrophages\u2014Unexpected contribution to tumor progression. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1638102"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1016\/j.celrep.2016.09.083","article-title":"Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3","volume":"17","author":"Alishekevitz","year":"2016","journal-title":"Cell Rep."},{"key":"ref_98","first-page":"2396","article-title":"Macrophage-mediated induction of drug-resistant variants in a mouse mammary tumor cell line","volume":"46","author":"Yamashina","year":"1986","journal-title":"Cancer Res."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Guo, Y., Tsai, H.I., Zhang, L., and Zhu, H. (2022). Mitochondrial DNA on Tumor-Associated Macrophages Polarization and Immunity. Cancers, 14.","DOI":"10.3390\/cancers14061452"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1126\/science.1203486","article-title":"Cancer immunoediting: Integrating immunity\u2019s roles in cancer suppression and promotion","volume":"331","author":"Schreiber","year":"2011","journal-title":"Science"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1038\/ni1102-991","article-title":"Cancer immunoediting: From immunosurveillance to tumor escape","volume":"3","author":"Dunn","year":"2002","journal-title":"Nat. Immunol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"e104920","DOI":"10.7554\/eLife.104920","article-title":"Trained immunity: A new player in cancer immunotherapy","volume":"14","author":"Li","year":"2025","journal-title":"eLife"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"4276","DOI":"10.7150\/thno.20999","article-title":"Noninvasive Imaging of CD206-Positive M2 Macrophages as an Early Biomarker for Post-Chemotherapy Tumor Relapse and Lymph Node Metastasis","volume":"7","author":"Zhang","year":"2017","journal-title":"Theranostics"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"4110","DOI":"10.1158\/1078-0432.CCR-18-0673","article-title":"Magnetic Resonance Imaging of Tumor-Associated Macrophages: Clinical Translation","volume":"24","author":"Aghighi","year":"2018","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1038\/s41598-018-37408-7","article-title":"Imaging endogenous macrophage iron deposits reveals a metabolic biomarker of polarized tumor macrophage infiltration and response to CSF1R breast cancer immunotherapy","volume":"9","author":"Leftin","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"eabo2952","DOI":"10.1126\/scitranslmed.abo2952","article-title":"Multispectral fluorine-19 MRI enables longitudinal and noninvasive monitoring of tumor-associated macrophages","volume":"14","author":"Croci","year":"2022","journal-title":"Sci. Transl. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6916\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:31:10Z","timestamp":1785904270000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6916"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,1]]},"references-count":106,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156916"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156916","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,1]]}}}