Kupffer cells and monocyte-derived macrophages in the pathogenesis and treatment of hepatocellular carcinoma

Abstract

Kupffer cells, the resident liver macrophages, are characterized by self-renewal capacity and extensive plasticity. Kupffer cells are involved in the regulation of several liver functions such as the maintenance of liver tolerance against antigens arriving at the liver through the portal vein, the autophagy and apoptosis of hepatocytes and other liver sinusoidal cells.and various metabolic functions such as iron homeostasis and lipid metabolism. In acute liver injury, Kupffer cells are involved in both liver damage and resolution. During chronic liver injury, resident and bone marrow-derived macrophages drive either the progression or resolution of fibrosis and cirrhosis. Inevitably, they are implicated in the initiation, progression or defense against hepatocellular carcinoma (HCC) as members of the tumor microenvironment together with bone marrow-derived macrophages. The present review describes the heterogeneity of Kupffer cells and liver-infiltrating macrophages, their functions and their participation in liver cancer with particular emphasis on factors modulating their pro-tumoral and anti-tumoral differentiation. The review is further focused on their involvement in HCC as they participate in the population of tumor-associated macrophages. Finally, the potential use of Kupffer cells and macrophages for the treatment of HCC, including the potentiation of immune checkpoint inhibitors, is presented.

Keywords

Kupffer cells / liver macrophages / hepatocellular carcinoma / liver macrophage heterogeneity6

References

[1] Li P,Feng Y.Global, regional, and national burden of hepatocellular carcinoma and contribution of nine modifiable risk factors across 185 countries/territories in 2022.Sci Bull2026;71:838-49

[2] Karageorgos SA,Koulentaki M.Long-term change in incidence and risk factors of cirrhosis and hepatocellular carcinoma in Crete, Greece: a 25-year study.Ann Gastroenterol2017;30:357-63 PMCID:PMC5411387

[3] Bilzer M,Gerbes AL.Role of Kupffer cells in host defense and liver disease.Liver Int2006;26:1175-86 PMCID:11933900

[4] Kupffer C.Ueber sternzellen der leber: briefliche mittheilung an Prof. Waldeyer.Archiv f mikrosk Anat1876;12:353-8

[5] Wake K.Karl Wilhelm Kupffer and his contributions to modern hepatology.Comp Hepatol2004;3:S2 PMCID:2410225

[6] Ueber intravasculäre Zellen in den Blutcapillaren der Leberacini.Arch f mikrosk Anat1899;55:420-6

[7] Underhill DM,Imhof BA,Bousso P.Élie Metchnikoff (1845-1916): celebrating 100 years of cellular immunology and beyond.Nat Rev Immunol2016;16:651-6

[8] Locati M,Mantovani A.Diversity, mechanisms, and significance of macrophage plasticity.Annu Rev Pathol2020;15:123-47 PMCID:PMC7176483

[9] Aegerter H,Crotta S.Influenza-induced monocyte-derived alveolar macrophages confer prolonged antibacterial protection.Nat Immunol2020;21:145-57 PMCID:PMC6983324

[10] Remmerie A,Thoné T.Osteopontin expression identifies a subset of recruited macrophages distinct from kupffer cells in the fatty liver.Immunity2020;53:641-57.e14 PMCID:PMC7501731

[11] Remmerie A,Scott CL.Macrophage subsets in obesity, aligning the liver and adipose tissue.Front Endocrinol2020;11:259 PMCID:PMC7201095

[12] Ju C.Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies.Cell Mol Immunol2016;13:316-27 PMCID:PMC4856798

[13] Gordon S.Tissue macrophages: heterogeneity and functions.BMC Biol2017;15:53 PMCID:PMC5492929

[14] Ydens E,Asselbergh B.Profiling peripheral nerve macrophages reveals two macrophage subsets with distinct localization, transcriptome and response to injury.Nat Neurosci2020;23:676-89 PMCID:PMC7611025

[15] Morgantini C,Li X.Liver macrophages regulate systemic metabolism through non-inflammatory factors.Nat Metab2019;1:445-59

[16] Perdiguero EG.The development and maintenance of resident macrophages.Nat Immunol2016;17:2-8 PMCID:PMC4950995

[17] Laviron M.Ontogeny of tumor-associated macrophages.Front Immunol2019;10:1799 PMCID:PMC6684758

[18] Gola A,Speranza E.Commensal-driven immune zonation of the liver promotes host defence.Nature2021;589:131-6 PMCID:PMC8691525

[19] Ben-Moshe S,Manco R.The spatiotemporal program of zonal liver regeneration following acute injury.Cell Stem Cell2022;29:973-89.e10

[20] Feng D,Wang Y,Mackowiak B.Characterisation of macrophages in healthy and diseased livers in mice: identification of necrotic lesion-associated macrophages.eGastroenterology2025;3:e100189 PMCID:PMC11979608

[21] Tran S,Poupel L.Impaired kupffer cell self-renewal alters the liver response to lipid overload during non-alcoholic steatohepatitis.Immunity2020;53:627-40.e5

[22] Daemen S,Kalugotla G.Dynamic shifts in the composition of resident and recruited macrophages influence tissue remodeling in NASH.Cell Rep2021;34:108626 PMCID:PMC7877246

[23] Rolot M,Javaux J.Recruitment of hepatic macrophages from monocytes is independent of IL-4Rα but is associated with ablation of resident macrophages in schistosomiasis.Eur J Immunol2019;49:1067-81

[24] Seidman JS,Sakai M.Niche-specific reprogramming of epigenetic landscapes drives myeloid cell diversity in nonalcoholic steatohepatitis.Immunity2020;52:1057-74.e7 PMCID:PMC7305990

[25] Fan X,Cui XH.Repopulating Kupffer cells originate directly from hematopoietic stem cells.Stem Cell Res Ther2023;14:351 PMCID:PMC10712046

[26] Guillot A.Liver macrophages: old dogmas and new insights.Hepatol Commun2019;3:730-43 PMCID:PMC6545867

[27] Sakai M,Seidman JS.Liver-derived signals sequentially reprogram myeloid enhancers to initiate and maintain Kupffer cell identity.Immunity2019;51:655-70.e8 PMCID:PMC6800814

[28] Liu Z,Chakarov S.Fate mapping via Ms4a3-expression history traces monocyte-derived cells.Cell2019;178:1509-25.e19 PMCID:12425476

[29] Guilliams M,Haest B.Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.Cell2022;185:379-96.e38 PMCID:PMC8809252

[30] Guilliams M.Liver macrophages in health and disease.Immunity2022;55:1515-29

[31] Miyamoto Y,Matsui T.Periportal macrophages protect against commensal-driven liver inflammation.Nature2024;629:901-9

[32] Blériot C,Dunsmore G.A subset of Kupffer cells regulates metabolism through the expression of CD36.Immunity2021;54:2101-16.e6

[33] De Simone G,Bleriot C.Identification of a Kupffer cell subset capable of reverting the T cell dysfunction induced by hepatocellular priming.Immunity2021;54:2089-100.e8 PMCID:PMC8459394

[34] Hume DA,Bonnavion R.Contamination of isolated mouse Kupffer cells with liver sinusoidal endothelial cells.Immunity2022;55:1139-40

[35] Beattie L,Mann J.Bone marrow-derived and resident liver macrophages display unique transcriptomic signatures but similar biological functions.J Hepatol2016;65:758-68 PMCID:PMC5028381

[36] Lee KJ,Han YH.Roles of heterogenous hepatic macrophages in the progression of liver diseases.BMB Rep2022;55:166-74 PMCID:9058466

[37] Guo W,Anagnostopoulos G.Notch signaling regulates macrophage-mediated inflammation in metabolic dysfunction-associated steatotic liver disease.Immunity2024;57:2310-27.e6

[38] Scott CL,De Baetselier P.Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells.Nat Commun2016;7:10321 PMCID:PMC4737801

[39] Bonnardel J,Gaublomme D.Stellate cells, hepatocytes, and endothelial cells imprint the Kupffer cell identity on monocytes colonizing the liver macrophage niche.Immunity2019;51:638-54.e9 PMCID:PMC6876284

[40] Elchaninov A,Kuznetsova M.Mimicking the cellular environment does not cause monocyte-derived macrophages to become phenotypically similar to Kupffer cells.Immunol Cell Biol2024;102:381-95

[41] Soysa R,Yuen S.Fetal origin confers radioresistance on liver macrophages via p21(cip1/WAF1).J Hepatol2019;71:553-62 PMCID:PMC12509797

[42] Iannacone M,Andreata F.Response to contamination of isolated mouse Kupffer cells with liver sinusoidal endothelial cells.Immunity2022;55:1141-2

[43] Ni M,Sosa R.T-cell immunoglobulin and mucin domain-containing protein-4 is critical for Kupffer cell homeostatic function in the activation and resolution of liver ischemia reperfusion injury.Hepatology2021;74:2118-32 PMCID:9060306

[44] Woolbright BL.The impact of sterile inflammation in acute liver injury.J Clin Transl Res2017;3:170-88 PMCID:5488807

[45] Zwicker C,Scott CL.Hepatic macrophage responses in inflammation, a function of plasticity, heterogeneity or both?.Front Immunol2021;12:690813 PMCID:PMC8220199

[46] MacParland SA,Ma XZ.Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations.Nat Commun2018;9:4383 PMCID:PMC6197289

[47] Aizarani N,Sagar .A human liver cell atlas reveals heterogeneity and epithelial progenitors.Nature2019;572:199-204 PMCID:PMC6687507

[48] Ramachandran P,Wilson-Kanamori JR.Resolving the fibrotic niche of human liver cirrhosis at single-cell level.Nature2019;575:512-8 PMCID:PMC6876711

[49] Andrews TS,Liu JC.Single-cell, single-nucleus, and spatial RNA sequencing of the human liver identifies cholangiocyte and mesenchymal heterogeneity.Hepatol Commun2022;6:821-40 PMCID:8948611

[50] Ramachandran P.Zonal control of liver inflammation is orchestrated by periportal Kupffer cells.J Hepatol2025;82:546-7

[51] Wu X,Roberto J.Human liver macrophage subsets defined by CD32.Front Immunol2020;11:2108 PMCID:PMC7546764

[52] Martrus G,Langeneckert AE.CD49a expression identifies a subset of intrahepatic macrophages in humans.Front Immunol2019;10:1247 PMCID:PMC6568245

[53] Fabre T,Christensen SM.Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation.Sci Immunol2023;8:eadd8945 PMCID:11898914

[54] Wen Y,Ju C.Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities.Cell Mol Immunol2021;18:45-56 PMCID:PMC7852525

[55] Lee WY,Wong CH.An intravascular immune response to Borrelia burgdorferi involves Kupffer cells and iNKT cells.Nat Immunol2010;11:295-302 PMCID:PMC5114121

[56] Gorgani NN,Katschke KJ Jr.Complement receptor of the Ig superfamily enhances complement-mediated phagocytosis in a subpopulation of tissue resident macrophages.J Immunol2008;181:7902-8

[57] Chaudhry S,Griesemer A.Immune cell trafficking to the liver.Transplantation2019;103:1323-37 PMCID:7044802

[58] Zhang JX,Huang H.TNF-α/TNFR1 regulates the polarization of Kupffer cells to mediate trichloroethylene-induced liver injury.Ecotoxicol Environ Saf2022;230:113141

[59] Strizova Z,Bartolini R.M1/M2 macrophages and their overlaps - myth or reality?.Clin Sci2023;137:1067-93 PMCID:10407193

[60] Sanin DE,Marinkovic E.A common framework of monocyte-derived macrophage activation.Sci Immunol2022;7:eabl7482 PMCID:PMC12362712

[61] Oshi M,Asaoka M.M1 macrophage and M1/M2 ratio defined by transcriptomic signatures resemble only part of their conventional clinical characteristics in breast cancer.Sci Rep2020;10:16554 PMCID:PMC7538579

[62] Cao F,Cheng Y,He Y.Multi-omics characteristics of tumor-associated macrophages in the tumor microenvironment of gastric cancer and their exploration of immunotherapy potential.Sci Rep2023;13:18265 PMCID:PMC10600170

[63] Cheng K,Zhu J,Liang H.Tumor-associated macrophages in liver cancer: from mechanisms to therapy.Cancer Commun2022;42:1112-40 PMCID:9648394

[64] Keirsse J,Geeraerts X,Raes G.The role of hepatic macrophages in liver metastasis.Cell Immunol2018;330:202-15

[65] Heymann F,Ludwig-Portugall I.Liver inflammation abrogates immunological tolerance induced by Kupffer cells.Hepatology2015;62:279-91

[66] Doherty DG.Immunity, tolerance and autoimmunity in the liver: a comprehensive review.J Autoimmun2016;66:60-75

[67] Breous E,Vandenberghe LH.Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver.Hepatology2009;50:612-21 PMCID:4380144

[68] Gong J,Liu J.Hepatocytes: a key role in liver inflammation.Front Immunol2022;13:1083780 PMCID:PMC9890163

[69] Campana L,Huch M.Liver regeneration and inflammation: from fundamental science to clinical applications.Nat Rev Mol Cell Biol2021;22:608-24

[70] Koyama Y.Liver inflammation and fibrosis.J Clin Invest2017;127:55-64 PMCID:5199698

[71] Shi H,Wang X.Efferocytosis in liver disease.JHEP Rep2024;6:100960 PMCID:PMC10792655

[72] Dixon LJ,Tang H,Nagy LE.Kupffer cells in the liver.Compr Physiol2013;3:785-97 PMCID:PMC4748178

[73] Li X,Lampert S.A conserved pathway of transdifferentiation in murine Kupffer cells.Eur J Immunol2021;51:2452-63

[74] Gaul S,Alegre F.Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis.J Hepatol2021;74:156-67 PMCID:PMC7749849

[75] Knorr J,Inzaugarat ME.Interleukin-18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis.Hepatology2023;77:1968-82 PMCID:PMC9984672

[76] Gan C,Tang C.Inflammasomes and pyroptosis of liver cells in liver fibrosis.Front Immunol2022;13:896473 PMCID:PMC9189314

[77] Vonderlin J,Sieweke M.The multifaceted roles of macrophages in NAFLD pathogenesis.Cell Mol Gastroenterol Hepatol2023;15:1311-24 PMCID:PMC10148157

[78] Guillot A,Silva Afonso M.Mapping the hepatic immune landscape identifies monocytic macrophages as key drivers of steatohepatitis and cholangiopathy progression.Hepatology2023;78:150-66

[79] Su SB,Xian XL.Interleukin-22 regulating Kupffer cell polarization through STAT3/Erk/Akt crosstalk pathways to extenuate liver fibrosis.Life Sci2021;264:118677

[80] Sakai Y,Ni Y.DPP-4 inhibition with anagliptin reduces lipotoxicity-induced insulin resistance and steatohepatitis in male mice.Endocrinology2020;161:bqaa139

[81] Cao S,Sehrawat TS.Regulation and functional roles of chemokines in liver diseases.Nat Rev Gastroenterol Hepatol2021;18:630-47 PMCID:PMC9036964

[82] She S,Chen P.Functional roles of chemokine receptor CCR2 and its ligands in liver disease.Front Immunol2022;13:812431 PMCID:PMC8913720

[83] Gao J,Liu M.Endothelial p300 promotes portal hypertension and hepatic fibrosis through C-C motif chemokine ligand 2-mediated angiocrine signaling.Hepatology2021;73:2468-83 PMCID:8102654

[84] Guo Y,Dai W.C-C motif chemokine receptor 2 inhibition reduces liver fibrosis by restoring the immune cell landscape.Int J Biol Sci2023;19:2572-87 PMCID:PMC10197881

[85] Lefere S,Tacke F.Targeting CCR2/5 in the treatment of nonalcoholic steatohepatitis (NASH) and fibrosis: opportunities and challenges.Expert Opin Investig Drugs2020;29:89-92

[86] Peiseler M,Zindel J.Kupffer cell-like syncytia replenish resident macrophage function in the fibrotic liver.Science2023;381:eabq5202

[87] Arteel GE.When is a Kupffer cell not a Kupffer cell? Novel insight into macrophage fate and function in hepatic fibrosis.J Leukoc Biol2024;115:415-6 PMCID:PMC12020053

[88] Sun K,Jing Y.Autophagy-deficient Kupffer cells promote tumorigenesis by enhancing mtROS-NF-κB-IL1α/β-dependent inflammation and fibrosis during the preneoplastic stage of hepatocarcinogenesis.Cancer Lett2017;388:198-207

[89] Ilyas G,Liu K.Macrophage autophagy limits acute toxic liver injury in mice through down regulation of interleukin-1β.J Hepatol2016;64:118-27 PMCID:PMC4691423

[90] Chen L,Xia S.Crosstalk between autophagy and innate immunity: a pivotal role in hepatic fibrosis.Front Pharmacol2022;13:891069 PMCID:PMC9152088

[91] Lodder J,Chobert MN.Macrophage autophagy protects against liver fibrosis in mice.Autophagy2015;11:1280-92 PMCID:PMC4590651

[92] Zhu J,Zhang L.IL-7 suppresses macrophage autophagy and promotes liver pathology in Schistosoma japonicum-infected mice.J Cell Mol Med2018;22:3353-63 PMCID:6010884

[93] Matuz-Mares D,Vilchis-Landeros MM.NOX as a therapeutic target in liver disease.Antioxidants2022;11:2038 PMCID:PMC9598239

[94] Herranz-Itúrbide M,Espinosa-Sotelo R,Fabregat I.The TGF-β/NADPH oxidases axis in the regulation of liver cell biology in health and disease.Cells2021;10:2312 PMCID:PMC8470857

[95] Nairz M,Swirski FK.“Pumping iron”-how macrophages handle iron at the systemic, microenvironmental, and cellular levels.Pflugers Arch2017;469:397-418 PMCID:5362662

[96] Scott CL.The role of Kupffer cells in hepatic iron and lipid metabolism.J Hepatol2018;69:1197-9 PMCID:PMC7611037

[97] Deppermann C,Peiseler M.Macrophage galactose lectin is critical for Kupffer cells to clear aged platelets.J Exp Med2020;217:e20190723 PMCID:PMC7144524

[98] Remmerie A.Macrophages and lipid metabolism.Cell Immunol2018;330:27-42 PMCID:PMC6108423

[99] Gao H,Bandyopadhyay G.MiR-690 treatment causes decreased fibrosis and steatosis and restores specific Kupffer cell functions in NASH.Cell Metab2022;34:978- 90.e4 PMCID:PMC9262870

[100] Coelho I,Macedo MP.Insights into macrophage/monocyte-endothelial cell crosstalk in the liver: a role for trem-2.J Clin Med2021;10:1248 PMCID:PMC8002813

[101] Gibert-Ramos A,Pastó R,Guixé-Muntet S.Sinusoidal communication in chronic liver disease.Clin Mol Hepatol2025;31:32-55 PMCID:PMC11791556

[102] Li W,Li L.Heterogeneity and function of kupffer cells in liver injury.Front Immunol2022;13:940867 PMCID:PMC9271789

[103] Elchaninov A,Menyailo E,Fatkhudinov T.An eye on Kupffer cells: development, phenotype and the macrophage niche.Int J Mol Sci2022;23:9868 PMCID:PMC9456487

[104] Musrati MA,Movahedi K.Ontogeny, functions and reprogramming of Kupffer cells upon infectious disease.Front Immunol2023;14:1238452 PMCID:PMC10485603

[105] Nusse Y.Liver macrophages: development, dynamics, and functions.Cell Mol Immunol2025;22:1178-89 PMCID:PMC12480653

[106] Cao M,Lan W.The roles of tissue resident macrophages in health and cancer.Exp Hematol Oncol2024;13:3 PMCID:PMC10790434

[107] Vogel A.Tissue-resident macrophages - early passengers or drivers in the tumor niche?.Curr Opin Biotechnol2023;83:102984

[108] Mulder K,Kong WT.Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease.Immunity2021;54:1883-900.e5

[109] Lazarov T,Cox N.Physiology and diseases of tissue-resident macrophages.Nature2023;618:698-707 PMCID:PMC10649266

[110] Elfstrum AK,Schwertfeger KL.Defining and targeting macrophage heterogeneity in the mammary gland and breast cancer.Cancer Med2024;13:e7053 PMCID:PMC10905685

[111] Hirano R,Shinke M.Tissue-resident macrophages are major tumor-associated macrophage resources, contributing to early TNBC development, recurrence, and metastases.Commun Biol2023;6:144 PMCID:PMC9898263

[112] Wu K,Li X.Redefining tumor-associated macrophage subpopulations and functions in the tumor microenvironment.Front Immunol2020;11:1731 PMCID:PMC7417513

[113] Xiang X,Lu D.Targeting tumor-associated macrophages to synergize tumor immunotherapy.Signal Transduct Target Ther2021;6:75 PMCID:PMC7900181

[114] Boutilier AJ.Macrophage polarization states in the tumor microenvironment.Int J Mol Sci2021;22:6995 PMCID:PMC8268869

[115] Gordon S.Alternative activation of macrophages: mechanism and functions.Immunity2010;32:593-604

[116] Galli SJ,Wynn TA.Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils.Nat Immunol2011;12:1035-44 PMCID:PMC3412172

[117] Griess B,Datta K.Scavenging reactive oxygen species selectively inhibits M2 macrophage polarization and their pro-tumorigenic function in part, via Stat3 suppression.Free Radic Biol Med2020;147:48-60 PMCID:PMC10035558

[118] Chi J,Liu D.Tissue-resident macrophages in cancer: friend or foe?.Cancer Med2024;13:e70387 PMCID:11533131

[119] Roh MS,Oyedeji C.Human Kupffer cells are cytotoxic against human colon adenocarcinoma.Surgery1990;108:400-4

[120] Heuff G,Betjes MG,Meijer S.Isolation and purification of large quantities of fresh human Kupffer cells, which are cytotoxic against colon carcinoma.Hepatology1995;21:740-5

[121] Kan Z,Lunderquist A,McCuskey RS.In vivo microscopy of hepatic metastases: dynamic observation of tumor cell invasion and interaction with Kupffer cells.Hepatology1995;21:487-94

[122] Song E,Ouyang N,Exton MS.Kupffer cells of cirrhotic rat livers sensitize colon cancer cells to Fas-mediated apoptosis.Br J Cancer2001;84:1265-71 PMCID:PMC2363876

[123] Lau WY,Lai PB.Induction of Fas and Fas ligand expression on malignant glioma cells by Kupffer cells, a potential pathway of antiliver metastases.J Surg Res2001;101:44-51

[124] Pearson HJ,Chamberlain J.The effect of Kupffer cell stimulation or depression on the development of liver metastases in the rat.Cancer Immunol Immunother1986;23:214-6 PMCID:11038908

[125] Valatas V,Manousou P.Secretion of inflammatory mediators by isolated rat Kupffer cells: the effect of octreotide.Regul Pept2004;120:215-25

[126] Aono K,Nakashima I,Miyachi M.Kupffer cells cytotoxicity against hepatoma cells is related to nitric oxide.Biochem Biophys Res Commun1994;201:1175-81

[127] Hourani T,Li W,Hadjigol S.Tumor associated macrophages: origin, recruitment, phenotypic diversity, and targeting.Front Oncol2021;11:788365 PMCID:PMC8722774

[128] Christofides A,Yeo A,Charest A.The complex role of tumor-infiltrating macrophages.Nat Immunol2022;23:1148-56 PMCID:PMC10754321

[129] Tian Z,Liu W,Wei L.Macrophages and hepatocellular carcinoma.Cell Biosci2019;9:79 PMCID:PMC6761725

[130] Cotechini T,Grossman A.Tissue-resident and recruited macrophages in primary tumor and metastatic microenvironments: potential targets in cancer therapy.Cells2021;10:960 PMCID:PMC8074766

[131] Wu JY,Hsieh YT.Cancer-derived succinate promotes macrophage polarization and cancer metastasis via succinate receptor.Mol Cell2020;77:213-27.e5

[132] Casari M,Deppermann C.Macrophages and platelets in liver fibrosis and hepatocellular carcinoma.Front Immunol2023;14:1277808 PMCID:PMC10728659

[133] Kuo TC,Harrabi O.Targeting the myeloid checkpoint receptor SIRPα potentiates innate and adaptive immune responses to promote anti-tumor activity.J Hematol Oncol2020;13:160 PMCID:PMC7706287

[134] Deng Z,Lazarov T.The nuclear factor ID3 endows macrophages with a potent anti-tumour activity.Nature2024;626:864-73 PMCID:PMC10881399

[135] Brodt P.Role of the microenvironment in liver metastasis: from pre- to prometastatic niches.Clin Cancer Res2016;22:5971-82

[136] Li J,Ge RL.The ligation between ERMAP, galectin-9 and dectin-2 promotes Kupffer cell phagocytosis and antitumor immunity.Nat Immunol2023;24:1813-24

[137] Wortzel I,Akano I.Unique structural configuration of EV-DNA primes Kupffer cell-mediated antitumor immunity to prevent metastatic progression.Nat Cancer2024;5:1815-33 PMCID:PMC12185067

[138] Jiang K,Fang Y.Exosomal ANGPTL1 attenuates colorectal cancer liver metastasis by regulating Kupffer cell secretion pattern and impeding MMP9 induced vascular leakiness.J Exp Clin Cancer Res2021;40:21 PMCID:PMC7792106

[139] Jin HR,Wang ZJ.Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics.J Hematol Oncol2023;16:103 PMCID:PMC10498649

[140] Ammarah U,Delfini M.From monocyte-derived macrophages to resident macrophages-how metabolism leads their way in cancer.Mol Oncol2024;18:1739-58 PMCID:11223613

[141] Nagy C.Time and demand are two critical dimensions of immunometabolism: the process of macrophage activation and the pentose phosphate pathway.Front Immunol2015;6:164 PMCID:PMC4389563

[142] Jha AK,Sergushichev A.Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization.Immunity2015;42:419-30 PMCID:12222308

[143] O’Neill LA.A broken krebs cycle in macrophages.Immunity2015;42:393-4

[144] Zaidi NE,Leow TC,Ibrahim K.Crosstalk between fatty acid metabolism and tumour-associated macrophages in cancer progression.Biomedicine2022;12:9-19 PMCID:9910230

[145] Liu Y,Gu H.Metabolic reprogramming in macrophage responses.Biomark Res2021;9:1 PMCID:PMC7786975

[146] Liu PS,Li X.α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming.Nat Immunol2017;18:985-94

[147] Van den Bossche J,Koehler ES.Pivotal Advance: Arginase-1-independent polyamine production stimulates the expression of IL-4-induced alternatively activated macrophage markers while inhibiting LPS-induced expression of inflammatory genes.J Leukoc Biol2012;91:685-99

[148] Van den Bossche J, O’Neill LA, Menon D. Macrophage Immunometabolism: where are we (going)?.Trends Immunol2017;38:395-406

[149] Sharma A,Dutertre CA.Onco-fetal reprogramming of endothelial cells drives immunosuppressive macrophages in hepatocellular carcinoma.Cell2020;183:377-94.e21 PMCID:8185081

[150] Casanova-Acebes M,Leader AM.Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells.Nature2021;595:578-84 PMCID:PMC8923521

[151] Shen KY,Xie SZ.Immunosuppressive tumor microenvironment and immunotherapy of hepatocellular carcinoma: current status and prospectives.J Hematol Oncol2024;17:25 PMCID:PMC11057182

[152] Mass E,Farlik M.Specification of tissue-resident macrophages during organogenesis.Science2016;353:aaf4238 PMCID:PMC5066309

[153] Li XY,Zhang JY,Gong JP.Kupffer cells suppress hepatocarcinogenesis and metastasis in tumor orthotopic implanted Kunming mice.Asian Pac J Cancer Prev2013;14:6393-8

[154] Hong GQ,Gong JP.Innate immune cells and their interaction with T cells in hepatocellular carcinoma.Oncol Lett2021;21:57 PMCID:7709558

[155] Prieto J.Inflammation, HCC and sex: IL-6 in the centre of the triangle.J Hepatol2008;48:380-1

[156] Naugler WE,Kim S.Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production.Science2007;317:121-4 PMCID:4578560

[157] Yuan Y,Li J.Mechanisms of tumor-associated macrophages affecting the progression of hepatocellular carcinoma.Front Pharmacol2023;14:1217400 PMCID:PMC10470150

[158] Lefere S,Van Vlierberghe H.Unveiling the depletion of Kupffer cells in experimental hepatocarcinogenesis through liver macrophage subtype-specific markers.J Hepatol2019;71:631-3

[159] Degroote H,Vandierendonck A.Characterization of the inflammatory microenvironment and hepatic macrophage subsets in experimental hepatocellular carcinoma models.Oncotarget2021;12:562-77 PMCID:PMC7984829

[160] Bosco MC.Macrophage polarization: Reaching across the aisle?.J Allergy Clin Immunol2019;143:1348-50

[161] Zhang Y,Gu J,Wu J.Role of tumor-associated macrophages in hepatocellular carcinoma: impact, mechanism, and therapy.Front Immunol2024;15:1429812 PMCID:PMC11335564

[162] Toledo B,Paniagua-Sancho M,Perán M.Deciphering the performance of macrophages in tumour microenvironment: a call for precision immunotherapy.J Hematol Oncol2024;17:44 PMCID:PMC11167803

[163] Wang Q.Revisiting TAM polarization: beyond M1- and M2-type TAM toward clinical precision in macrophage-targeted therapy.Exp Mol Pathol2025;143:104982

[164] Yang Y,Chen Y.Crosstalk between hepatic tumor cells and macrophages via Wnt/β-catenin signaling promotes M2-like macrophage polarization and reinforces tumor malignant behaviors.Cell Death Dis2018;9:793 PMCID:PMC6052107

[165] Ma RY,Qian BZ.Macrophage diversity in cancer revisited in the era of single-cell omics.Trends Immunol2022;43:546-63

[166] Guo S,Guo C.Tumour-associated macrophages heterogeneity drives resistance to clinical therapy.Expert Rev Mol Med2022;24:e17 PMCID:PMC9884773

[167] Li JQ,Wang YC.Distinct patterns and prognostic values of tumor-infiltrating macrophages in hepatocellular carcinoma and gastric cancer.J Transl Med2017;15:37 PMCID:PMC5312581

[168] Lu Y,Quan C.A single-cell atlas of the multicellular ecosystem of primary and metastatic hepatocellular carcinoma.Nat Commun2022;13:4594 PMCID:PMC9357016

[169] Xiao N,Li K.Blocking siglec-10^hi tumor-associated macrophages improves anti-tumor immunity and enhances immunotherapy for hepatocellular carcinoma.Exp Hematol Oncol2021;10:36 PMCID:8191104

[170] Ng HHM,Goh S.Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma.J Immunother Cancer2020;8:e000987 PMCID:PMC7451957

[171] Cui X,Wei S.Hepatocellular carcinoma-derived FOXO1 inhibits tumor progression by suppressing IL-6 secretion from macrophages.Neoplasia2023;40:100900 PMCID:PMC10123375

[172] Wu J,Salcedo R,Trinchieri G.The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma.Cancer Res2012;72:3977-86 PMCID:3694446

[173] Dou L,He X.Macrophage phenotype and function in liver disorder.Front Immunol2019;10:3112 PMCID:PMC6997484

[174] Thomann S,Wei T.YAP-induced Ccl2 expression is associated with a switch in hepatic macrophage identity and vascular remodelling in liver cancer.Liver Int2021;41:3011-23

[175] Vanderborght B,Gijbels E.Transient Kupffer cell depletion and subsequent replacement by infiltrating monocyte-derived cells does not alter the induction or progression of hepatocellular carcinoma.Int J Cancer2023;152:2615-28

[176] Du L,Xin B.Shp2 deficiency in Kupffer cells and hepatocytes aggravates hepatocarcinogenesis by recruiting non-Kupffer macrophages.Cell Mol Gastroenterol Hepatol2023;15:1351-69 PMCID:PMC10140795

[177] Li X,Miao X.Integrated single cell analysis reveals an atlas of tumor associated macrophages in hepatocellular carcinoma.Inflammation2024;47:2077-93

[178] Zhang M,Zhang Q.Alpha fetoprotein promotes polarization of macrophages towards M2-like phenotype and inhibits macrophages to phagocytize hepatoma cells.Front Immunol2023;14:1081572 PMCID:PMC9995430

[179] Yu H,Zheng S.Hepatocellular carcinoma cell-derived exosomal miR-21-5p induces macrophage M2 polarization by targeting RhoB.Int J Mol Sci2023;24:4593 PMCID:PMC10003272

[180] Sun JL,Xu RC.Tumor cell-imposed iron restriction drives immunosuppressive polarization of tumor-associated macrophages.J Transl Med2021;19:347 PMCID:PMC8361643

[181] Yang S,Xu Y.OIT3 mediates macrophage polarization and facilitates hepatocellular carcinoma progression.Cancer Immunol Immunother2022;71:2677-89 PMCID:PMC10992929

[182] Zhao J,Liu Y.Single-cell RNA sequencing reveals the heterogeneity of liver-resident immune cells in human.Cell Discov2020;6:22 PMCID:PMC7186229

[183] Sun Y,Zhong Y.Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma.Cell2021;184:404-21.e16

[184] Zhang Q,Luo N.Landscape and dynamics of single immune cells in hepatocellular carcinoma.Cell2019;179:829-45.e20 PMCID:11194221

[185] Sas Z,Weinhäuser I.Tumor microenvironment of hepatocellular carcinoma: challenges and opportunities for new treatment options.Int J Mol Sci2022;23:3778 PMCID:PMC8998420

[186] Capece D,Verzella D.The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumor-associated macrophages.Biomed Res Int2013;2013:187204 PMCID:PMC3591180

[187] Yu M,Wang H.Tumor‑associated macrophages activated in the tumor environment of hepatocellular carcinoma: characterization and treatment (Review).Int J Oncol2024;65:100 PMCID:PMC11387121

[188] Ajith A,Bouzin C. Progression to fibrosis and hepatocellular carcinoma in DEN CCl₄ liver mice, is associated with macrophage and striking regulatory T cells infiltration. Front Immunol 2025;16:1601215.[PMID:40698077 DOI:10.3389/fimmu.2025.1601215 PMCID:12279789] Caution!

[189] Malehmir M,Gallage S.Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer.Nat Med2019;25:641-55 PMCID:PMC12452109

[190] Roderburg C,Demir M,Tacke F.The role of the innate immune system in the development and treatment of hepatocellular carcinoma.Hepat Oncol2020;7:HEP17 PMCID:PMC7137177

[191] Chen J,Yu XJ.Macrophages induce CD47 upregulation via IL-6 and correlate with poor survival in hepatocellular carcinoma patients.Oncoimmunology2019;8:e1652540 PMCID:6791434

[192] Li YW,Fan J.Tumor-infiltrating macrophages can predict favorable prognosis in hepatocellular carcinoma after resection.J Cancer Res Clin Oncol2009;135:439-49 PMCID:PMC12160305

[193] Zhang Y,Jiang ZZ,Wu Y.CD169 identifies an anti-tumour macrophage subpopulation in human hepatocellular carcinoma.J Pathol2016;239:231-41

[194] Ding T,Wang F.High tumor-infiltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection.Hum Pathol2009;40:381-9

[195] Kang TW,Woller N.Senescence surveillance of pre-malignant hepatocytes limits liver cancer development.Nature2011;479:547-51 PMCID:8651290

[196] Liu N,Steer CJ.MicroRNA-206 promotes the recruitment of CD8⁺ T cells by driving M1 polarisation of Kupffer cells.Gut2022;71:1642-55 PMCID:9279850

[197] Hastir JF,Larbanoix L.Hepatocarcinoma induces a tumor necrosis factor-dependent Kupffer cell death pathway that favors its proliferation upon partial hepatectomy.Front Oncol2020;10:547013 PMCID:PMC7597592

[198] Tian Y,Fan M.A miRNA-mediated attenuation of hepatocarcinogenesis in both hepatocytes and Kupffer cells.Mol Ther Nucleic Acids2022;30:1-12 PMCID:PMC9471972

[199] Herman AB,Gorospe M.Integrated lncRNA function upon genomic and epigenomic regulation.Mol Cell2022;82:2252-66 PMCID:PMC9219586

[200] Wu H,Wang A.LncRNA FTX represses the progression of non-alcoholic fatty liver disease to hepatocellular carcinoma via regulating the M1/M2 polarization of Kupffer cells.Cancer Cell Int2020;20:266 PMCID:PMC7315496

[201] Wei Q,Huang Z.LncRNA MEG3 inhibits tumor progression by modulating macrophage phenotypic polarization via miR-145-5p/DAB2 axis in hepatocellular carcinoma.J Hepatocell Carcinoma2023;10:1019-35 PMCID:10329916

[202] Hou ZH,Fu XY,Liu SP.Long non-coding RNA MALAT1 promotes angiogenesis and immunosuppressive properties of HCC cells by sponging miR-140.Am J Physiol Cell Physiol2020;318:C649-63

[203] Tian X,Yang Y.Long noncoding RNA LINC00662 promotes M2 macrophage polarization and hepatocellular carcinoma progression via activating Wnt/β-catenin signaling.Mol Oncol2020;14:462-83 PMCID:6998656

[204] Ye Y,Lai Y.Long non-coding RNA cox-2 prevents immune evasion and metastasis of hepatocellular carcinoma by altering M1/M2 macrophage polarization.J Cell Biochem2018;119:2951-63

[205] Wang X,Zhao W.Long non-coding RNA GAS5 overexpression inhibits M2-like polarization of tumour-associated macrophages in SMCC-7721 cells by promoting PTEN expression.Int J Exp Pathol2020;101:215-22 PMCID:7691218

[206] Xu M,Weng J.Tumor associated macrophages-derived exosomes facilitate hepatocellular carcinoma malignance by transferring lncMMPA to tumor cells and activating glycolysis pathway.J Exp Clin Cancer Res2022;41:253 PMCID:PMC9389814

[207] Li X,Wu M.Regulation of macrophage activation and polarization by HCC-derived exosomal lncRNA TUC339.Int J Mol Sci2018;19:2958 PMCID:PMC6213212

[208] Lv S,Li L.Extracellular vesicular lncRNA FAL1 promotes hepatocellular carcinoma cell proliferation and invasion by inducing macrophage M2 polarization.J Physiol Biochem2023;79:669-82

[209] Ai JH,Dai SJ,Huang ZJ.Exosomal lncRNA HEIH, an essential communicator for hepatocellular carcinoma cells and macrophage M2 polarization through the miR-98-5p/STAT3 axis.J Biochem Mol Toxicol2024;38:e23686

[210] Wang X,Dong K,Gong J.Exosomal lncRNA HMMR-AS1 mediates macrophage polarization through miR-147a/ARID3A axis under hypoxia and affects the progression of hepatocellular carcinoma.Environ Toxicol2022;37:1357-72

[211] Zhou J,Xu L,Zhou W.Tumor-derived extracellular vesicles containing long noncoding RNA PART1 exert oncogenic effect in hepatocellular carcinoma by polarizing macrophages into M2.Dig Liver Dis2022;54:543-53

[212] Ye Y,Wang G.lncRNA miR4458HG modulates hepatocellular carcinoma progression by activating m6A-dependent glycolysis and promoting the polarization of tumor-associated macrophages.Cell Mol Life Sci2023;80:99 PMCID:PMC11072995

[213] Zhao S,Hu L.Long non-coding rnas as key modulators of the immune microenvironment in hepatocellular carcinoma: implications for Immunotherapy.Front Immunol2025;16:1523190 PMCID:PMC12061944

[214] Ghorbani Vanan A,Ghorbaninezhad F.Macrophage polarization in hepatocellular carcinoma: a lncRNA-centric perspective on tumor progression and metastasis.Clin Exp Med2025;25:173 PMCID:PMC12104118

[215] Delire B,Lemoine P,Stärkel P.Chronic liver injury promotes hepatocarcinoma cell seeding and growth, associated with infiltration by macrophages.Cancer Sci2018;109:2141-52 PMCID:PMC6029836

[216] Huang Y,Zhou J,Qian X.The role of tumor associated macrophages in hepatocellular carcinoma.J Cancer2021;12:1284-94 PMCID:PMC7847664

[217] Chang CP,Lee PH.Targeting NFKB by autophagy to polarize hepatoma-associated macrophage differentiation.Autophagy2013;9:619-21 PMCID:PMC3627680

[218] Sugisawa R,Hiramoto E.Independent modes of disease repair by AIM protein distinguished in AIM-felinized mice.Sci Rep2018;8:13157 PMCID:PMC6120884

[219] Zhang J,Zhao Z.SLC16A3 as an immunosuppressive Kupffer cell marker predicts poor prognosis in HBV-positive hepatocellular carcinoma.J Transl Med2025;23:988 PMCID:PMC12406350

[220] Ohno A,Haruyama Y.Aberrant expression of monocarboxylate transporter 4 in tumour cells predicts an unfavourable outcome in patients with hepatocellular carcinoma.Liver Int2014;34:942-52

[221] Alves VA,Morais-Santos F,Longatto-Filho A.Characterization of monocarboxylate transporter activity in hepatocellular carcinoma.World J Gastroenterol2014;20:11780-7 PMCID:PMC4155368

[222] Ioannou GN.The role of cholesterol in the pathogenesis of NASH.Trends Endocrinol Metab2016;27:84-95

[223] Escobedo-calvario A,Simoni-nieves A.Tumor immune microenvironment modulation by cholesterol in hepatocellular carcinoma.Explor Dig Dis2022;1:21-39

[224] Simoni-Nieves A,Chávez-Rodríguez L.The consumption of cholesterol-enriched diets conditions the development of a subtype of HCC with high aggressiveness and poor prognosis.Cancers2021;13:1721 PMCID:PMC8038696

[225] Goossens P,Etzerodt A.Membrane cholesterol efflux drives tumor-associated macrophage reprogramming and tumor progression.Cell Metab2019;29:1376-89.e4 PMCID:12222308

[226] Yang Y,To KKW,Wang F.Tumor-associated macrophages remodel the suppressive tumor immune microenvironment and targeted therapy for immunotherapy.J Exp Clin Cancer Res2025;44:145 PMCID:PMC12083052

[227] Sheng J,Wang L.Topological analysis of hepatocellular carcinoma tumour microenvironment based on imaging mass cytometry reveals cellular neighbourhood regulated reversely by macrophages with different ontogeny.Gut2022;71:1176-91

[228] Liu W,Yao Q.In situ expansion and reprogramming of Kupffer cells elicit potent tumoricidal immunity against liver metastasis.J Clin Invest2023;133:e157937 PMCID:10104906

[229] Siwicki M,Messemaker M.Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy.Sci Immunol2021;6:eabi7083 PMCID:PMC8845079

[230] Xu W,Guo Y,Qian H.Targeting tumor associated macrophages in hepatocellular carcinoma.Biochem Pharmacol2022;199:114990

[231] Giannone G,Genta S.Immuno-metabolism and microenvironment in cancer: key players for immunotherapy.Int J Mol Sci2020;21:4414 PMCID:PMC7352562

[232] Lemaitre L,Suresh A.Spatial analysis reveals targetable macrophage-mediated mechanisms of immune evasion in hepatocellular carcinoma minimal residual disease.Nat Cancer2024;5:1534-56 PMCID:PMC12258040

[233] Weng J,Hu Z.Repolarization of immunosuppressive macrophages by targeting SLAMF7-regulated CCL2 signaling sensitizes hepatocellular carcinoma to immunotherapy.Cancer Res2024;84:1817-33

[234] Zhang Y,Lu J.The influence of biophysical niche on tumor-associated macrophages in liver cancer.Hepatol Commun2024;8:e0569 PMCID:PMC11524744

[235] Li M,Zhu J,Liang S.Targeting tumor-associated macrophages for cancer treatment.Cell Biosci2022;12:85 PMCID:PMC9172100

[236] Liu X,Zuo C.Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity.Cancer Cell2023;41:1073-90.e12 PMCID:PMC10281762

[237] Liu F,Zhang Y.Targeting tumor-associated macrophages to overcome immune checkpoint inhibitor resistance in hepatocellular carcinoma.J Exp Clin Cancer Res2025;44:227 PMCID:PMC12323087

[238] Chen M,Lin X,Wu H.Downregulation of triggering receptor expressed on myeloid cells 1 inhibits invasion and migration of liver cancer cells by mediating macrophage polarization.Oncol Rep2021;45:37

[239] Yang Y,Qu M.Exploring the potential of treating chronic liver disease targeting the PI3K/Akt pathway and polarization mechanism of macrophages.Heliyon2023;9:e17116 PMCID:PMC10361319

[240] Ren L,Zhang SX,Lv SX.Pharmacological inhibition or silencing of TREM1 restrains HCC cell metastasis by inactivating TLR/PI3K/AKT signaling.Cell Biochem Biophys2024;82:2673-85

[241] Song M,Gu HS.Ganoderma lucidum spore polysaccharide inhibits the growth of hepatocellular carcinoma cells by altering macrophage polarity and induction of apoptosis.J Immunol Res2021;2021:6696606 PMCID:PMC7954632

[242] Lu S,Huang X.Cantharidin exerts anti-hepatocellular carcinoma by miR-214 modulating macrophage polarization.Int J Biol Sci2014;10:415-25 PMCID:PMC3979994

[243] Min L,Qi H.Astragaloside IV inhibits the progression of liver cancer by modulating macrophage polarization through the TLR4/NF-κB/STAT3 signaling pathway.Am J Transl Res2022;14:1551-66 PMCID:PMC8991133

[244] Bannister ME,Shetty S.The role of macrophages in hepatocellular carcinoma and their therapeutic potential.Int J Mol Sci2024;25:13167 PMCID:PMC11641991

[245] Cancer Genome Atlas Research Network. Electronic address: [e-mail]; Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma.Cell2017;169:1327-41.e23 PMCID:PMC5680778

[246] Cai N,Ma Y.Targeting MMP9 in CTNNB1 mutant hepatocellular carcinoma restores CD8⁺ T cell-mediated antitumour immunity and improves anti-PD-1 efficacy.Gut2024;73:985-99 PMCID:11103337

[247] Zhao J,Yao X.Targeting TFAM downregulation mediated mtDNA-NLRP3 pathway suppresses TAM infiltration and HCC progression.Oncogene2025;44:2956-69

[248] Zhu CX,Chen L.Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8⁺ T cells in hepatocellular carcinoma.J Hepatol2024;81:690-703

[249] Fu X,Wang Z.Macrophage polarization in the tumor microenvironment of hepatocellular carcinoma: from mechanistic insights to translational therapies.Cancer Control2025;32:10732748251406674 PMCID:PMC12709032

[250] Tan J,Liu T.TREM2⁺ macrophages suppress CD8⁺ T-cell infiltration after transarterial chemoembolisation in hepatocellular carcinoma.J Hepatol2023;79:126-40

[251] Yang H,Zhao K.Targeting the adenosine signaling pathway in macrophages for cancer immunotherapy.Hum Immunol2024;85:110774

[252] Karimova AF,Suezov R.Immunometabolism of tumor-associated macrophages: a therapeutic perspective.Eur J Cancer2025;220:115332

[253] Li D.Emerging therapeutics targeting tumor-associated macrophages for the treatment of solid organ cancers.Expert Opin Emerg Drugs2025;30:109-47 PMCID:PMC12232465

[254] Duan Z.Targeting macrophages in cancer immunotherapy.Signal Transduct Target Ther2021;6:127 PMCID:PMC7994399

[255] Yang S,Jia J.Advances in engineered macrophages: a new frontier in cancer immunotherapy.Cell Death Dis2024;15:238 PMCID:PMC10985090

[256] Na YR,Seok SH.A new era of macrophage-based cell therapy.Exp Mol Med2023;55:1945-54 PMCID:PMC10545778

[257] Etzerodt A,Maniecki M.Specific targeting of CD163⁺ TAMs mobilizes inflammatory monocytes and promotes T cell-mediated tumor regression.J Exp Med2019;216:2394-411 PMCID:6781002

[258] Mitsui Y.Functional diversity of disorder-specific macrophages involved in various diseases.Inflamm Regen2025;45:29 PMCID:PMC12487080