Review Article
 

Engineering and Targeting Macrophages for Cancer Therapy

Abstract

Macrophages are tissue-resident phagocytic cells of the innate immune system that differentiate from circulating blood monocytes and play complex roles in both physiological and pathological conditions. Emerging research indicates that macrophages exhibit diverse phenotypic characteristics and considerable functional plasticity in both physiological and pathological states, including cancer. Macrophages play a complex role in the development and progression of cancer. A model has been proposed that distinguishes between M1 and M2 macrophages in cancer, with M1 macrophages exhibiting antitumor effects, while M2 macrophages have tumor-supportive and immunosuppressive functions. The selective activation of beneficial macrophage populations and the targeted inhibition or re-polarization of tumor-promoting macrophages have shown significant potential for cancer treatment. Due to their intrinsic response to inflammation and their ability to overcome physical barriers, macrophages and their derivatives, including membranes and extracellular vesicles (EVs), are considered sophisticated carriers for drug delivery, enhancing tumor targeting and therapeutic efficacy. This review details recent advances in the development of macrophages for drug delivery and their targeted use of macrophages in cancer therapy. This review aims to provide a comprehensive overview of the capabilities of macrophages in cancer treatment.

1. Cendrowicz E, Sas Z, Bremer E, Rygiel TP. The Role of Macrophages in Cancer Development and Therapy. Cancers (Basel). 2021;13(8).
2. Mantovani A, Allavena P, Marchesi F, Garlanda C. Macrophages as tools and targets in cancer therapy. Nat Rev Drug Discovery. 2022;21(11):799–820.
3. Gharavi AT, Hanjani NA, Movahed E, Doroudian M. The role of macrophage subtypes and exosomes in immunomodulation. Cell Mol Biol Lett. 2022;27(1):83.
4. Cheng S, Li Z, Gao R, Xing B, Gao Y, Yang Y, et al. A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell. 2021;184(3):792–809.e23.
5. Mulder K, Patel AA, Kong WT, Piot C, Halitzki E, Dunsmore G, et al. Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease. Immunity. 2021;54(8):1883–900.e5.
6. Lahmar Q, Keirsse J, Laoui D, Movahedi K, Van Overmeire E, Van Ginderachter J. Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment. Biochim Biophys Acta. 2015;1865.
7. Carrizo GE, Lin P, Lee SH, Shenderov K, Blériot C, Cha M, et al. The transition from monocyte to tissue-resident macrophage requires DHPS. Nature. 2026;651(8106):763–74.
8. Lee H-W, Choi H-J, Ha S-J, Lee K-T, Kwon Y-G. Recruitment of monocytes/macrophages in different tumor microenvironments. Biochim Biophys Acta. 2013;1835(2):170–9.
9. Ying K, Zhu Y, Wan J, Zhan C, Wang Y, Xie B, et al. Macrophage membrane-biomimetic adhesive polycaprolactone nanocamptothecin for improving cancer-targeting efficiency and impairing metastasis. Bioact Mater. 2023;20:449–62.
10. Wang Y, Zhao M, Liu S, Guo J, Lu Y, Cheng J, et al. Macrophage-derived extracellular vesicles: diverse mediators of pathology and therapeutics in multiple diseases. Cell Death Dis. 2020;11(10):924.
11. Noy R, Pollard Jeffrey W. Tumor-Associated Macrophages: From Mechanisms to Therapy. Immunity. 2014;41(1):49–61.
12. Cassetta L, Pollard JW. Targeting macrophages: therapeutic approaches in cancer. Nat Rev Drug Discovery. 2018;17(12):887–904.
13. Murray PJ. Macrophage polarization. Annual review of physiology. 2017;79(1):541–66.
14. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787–95.
15. Locati M, Curtale G, Mantovani A. Diversity, mechanisms, and significance of macrophage plasticity. Annu Rev Pathol. 2020;15(1):123–47.
16. Wang S, Wang J, Chen Z, Luo J, Guo W, Sun L, et al. Targeting M2-like tumor-associated macrophages is a potential therapeutic approach to overcome antitumor drug resistance. npj Precision Oncol. 2024;8(1):31.
17. Eren CY, Gurer HG, Gursoy OO, Sezer CV. Antitumor Effects of L-citrulline on Hela Cervical Cancer Cell Lines. Anticancer Agents Med Chem. 2022;22(18):3157–62.
18. Kim S-H, Roszik J, Grimm EA, Ekmekcioglu S. Impact of l-Arginine Metabolism on Immune Response and Anticancer Immunotherapy. Front Oncol. 2018;8.
19. Bruns H, Büttner M, Fabri M, Mougiakakos D, Bittenbring JT, Hoffmann MH, et al. Vitamin D–dependent induction of cathelicidin in human macrophages results in cytotoxicity against high-grade B cell lymphoma. Sci Translat Med. 2015;7(282):282ra47–ra47.
20. Lin L, Chen YS, Yao YD, Chen JQ, Chen JN, Huang SY, et al. CCL18 from tumor-associated macrophages promotes angiogenesis in breast cancer. Oncotarget. 2015;6(33):34758–73.
21. Fu C, Jiang L, Hao S, Liu Z, Ding S, Zhang W, et al. Activation of the IL-4/STAT6 Signaling Pathway Promotes Lung Cancer Progression by Increasing M2 Myeloid Cells. Front Immunol. 2019;10.
22. Zhang F, Li P, Liu S, Yang M, Zeng S, Deng J, et al. β-Catenin-CCL2 feedback loop mediates crosstalk between cancer cells and macrophages that regulates breast cancer stem cells. Oncogene. 2021;40(39):5854–65.
23. Zhang X, Chen L, Dang W-q, Cao M-f, Xiao J-f, Lv S-q, et al. CCL8 secreted by tumor-associated macrophages promotes invasion and stemness of glioblastoma cells via ERK1/2 signaling. Laboratory Invest. 2020;100(4):619–29.
24. Wan S, Zhao E, Kryczek I, Vatan L, Sadovskaya A, Ludema G, et al. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology. 2014;147(6):1393–404.
25. Yang J, Liao D, Chen C, Liu Y, Chuang T-H, Xiang R, et al. Tumor-associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox-2 signaling pathway. Stem cells. 2013;31(2):248–58.
26. Hagemann T, Robinson SC, Schulz M, Trümper L, Balkwill FR, Binder C. Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-α dependent up-regulation of matrix metalloproteases. Carcinogenesis. 2004;25(8):1543–9.
27. Liu C, Zhang W, Wang J, Si T, Xing W. Tumor-associated macrophage-derived transforming growth factor-β promotes colorectal cancer progression through HIF1-TRIB3 signaling. Cancer Sci. 2021;112(10):4198–207.
28. Atri C, Guerfali FZ, Laouini D. Role of human macrophage polarization in inflammation during infectious diseases. Int J Mol Sci. 2018;19(6):1801.
29. Funes SC, Rios M, Escobar‐Vera J, Kalergis AM. Implications of macrophage polarization in autoimmunity. Immunology. 2018;154(2):186–95.
30. Wu H, Xu JB, He YL, Peng JJ, Zhang XH, CHEN CQ, et al. Tumor‐associated macrophages promote angiogenesis and lymphangiogenesis of gastric cancer. J Surgical Oncol. 2012;106(4):462–8.
31. Coulis G, Jaime D, Guerrero-Juarez C, Kastenschmidt JM, Farahat PK, Nguyen Q, et al. Single-cell and spatial transcriptomics identify a macrophage population associated with skeletal muscle fibrosis. bioRxiv. 2023.
32. Cheng S, Li Z, Gao R, Xing B, Gao Y, Yang Y, et al. A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell. 2021;184(3):792–809. e23.
33. Block A, Liu X, Zhang D, Adebowale K. Engineering macrophages for cancer immunotherapy: emerging insights and therapeutic potential. NPJ Biomed Innov. 2026;3(1):18.
34. D'Ambrosio M, Warasnhe K, Eldesouki MH, Joshi V, Beyder A, Cipriani G. Macrophage mechanobiology: from sensing to disease. Front Immunol. 2026;17:1812501.
35. Yang Z, Li R, An L, Zhang X, Cheng J, Cai Y, et al. Tumor Mechanobiology-Inspired Nanomechanics: Piezo1 Mediated Tumor-Associated Macrophages Reprogramming and Exosome-Driven Immune Amplification. ACS Nano. 2025;19(49):41746–64.
36. Mantovani A, Bottazzi B, Colotta F, Sozzani S, Ruco L. The origin and function of tumor-associated macrophages. Immunol Today. 1992;13(7):265–70.
37. Mantovani A. Effects on in vitro tumor growth of murine macrophages isolated from sarcoma lines differing in immunogenicity and metastasizing capacity. Int J Cancer. 1978;22(6):741–6.
38. Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14(7):399–416.
39. Fridman WH, Zitvogel L, Sautès–Fridman C, Kroemer G. The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol. 2017;14(12):717–34.
40. Tokunaga R, Zhang W, Naseem M, Puccini A, Berger MD, Soni S, et al. CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation–a target for novel cancer therapy. Cancer Treat Rev. 2018;63:40–7.
41. Wang F, Zhang S, Jeon R, Vuckovic I, Jiang X, Lerman A, et al. Interferon gamma induces reversible metabolic reprogramming of M1 macrophages to sustain cell viability and pro-inflammatory activity. EBioMedicine. 2018;30:303–16.
42. Han J, Dong L, Wu M, Ma F. Dynamic polarization of tumor-associated macrophages and their interaction with intratumoral T cells in an inflamed tumor microenvironment: from mechanistic insights to therapeutic opportunities. Front Immunol. 2023;Volume 14 - 2023.
43. Li M, Jiang P, Wei S, Wang J, Li C. The role of macrophages-mediated communications among cell compositions of tumor microenvironment in cancer progression. Front Immunol. 2023;14:1113312.
44. Sheban F. It takes two to tango: the role of tumor-associated macrophages in T cell-directed immune checkpoint blockade therapy. Front Immunol. 2023;Volume 14 - 2023.
45. Yang Y-l, Yang F, Huang Z-q, Li Y-y, Shi H-y, Sun Q, et al. T cells, NK cells, and tumor-associated macrophages in cancer immunotherapy and the current state of the art of drug delivery systems. Front Immunol. 2023;Volume 14 - 2023.
46. Gordon SR, Maute RL, Dulken BW, Hutter G, George BM, McCracken MN, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature. 2017;545(7655):495–9.
47. Lin H, Wei S, Hurt EM, Green MD, Zhao L, Vatan L, et al. Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression. J Clin Invest. 2018;128(2):805–15.
48. Peranzoni E, Lemoine J, Vimeux L, Feuillet V, Barrin S, Kantari-Mimoun C, et al. Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment. Proc Natl Acad Sci U S A. 2018;115(17):E4041–e50.
49. Rameshbabu S, Labadie BW, Argulian A, Patnaik A. Targeting innate immunity in cancer therapy. Vaccines. 2021;9(2):138.
50. Chen S, Saeed AFUH, Liu Q, Jiang Q, Xu H, Xiao GG, et al. Macrophages in immunoregulation and therapeutics. Signal Transduct Target Ther. 2023;8(1):207.
51. Pascual-García M, Bonfill-Teixidor E, Planas-Rigol E, Rubio-Perez C, Iurlaro R, Arias A, et al. LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy. Nat Commun. 2019;10(1):2416.
52. House IG, Savas P, Lai J, Chen AX, Oliver AJ, Teo ZL, et al. Macrophage-derived CXCL9 and CXCL10 are required for antitumor immune responses following immune checkpoint blockade. Clinical Cancer Res. 2020;26(2):487–504.
53. Litchfield K, Reading JL, Puttick C, Thakkar K, Abbosh C, Bentham R, et al. Meta-analysis of tumor-and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell. 2021;184(3):596–614. e14.
54. Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, et al. IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127(8):2930–40.
55. Lim RJ, Salehi-Rad R, Tran LM, Oh MS, Dumitras C, Crosson WP, et al. CXCL9/10-engineered dendritic cells promote T cell activation and enhance immune checkpoint blockade for lung cancer. Cell Rep Medi. 2024;5(4).
56. Paul S, Chhatar S, Mishra A, Lal G. Natural killer T cell activation increases iNOS<sup>+</sup>CD206<sup>-</sup> M1 macrophage and controls the growth of solid tumor. J Immunol Therapy Cancer. 2019;7(1):208.
57. Kashfi K, Kannikal J, Nath N. Macrophage Reprogramming and Cancer Therapeutics: Role of iNOS-Derived NO. Cells. 2021;10(11).
58. Kang B, Xing Q, Huang Y, Lin H, Peng J, Zhang Z, et al. Large-scale generation of IL-12 secreting macrophages from human pluripotent stem cells for cancer therapy. Mol Therapy Methods Clin Develop. 2024;32(1).
59. Watkins SK, Egilmez NK, Suttles J, Stout RD. IL-12 Rapidly Alters the Functional Profile of Tumor-Associated and Tumor-Infiltrating Macrophages In Vitro and In Vivo1. J Immunol. 2007;178(3):1357–62.
60. Chanmee T, Ontong P, Konno K, Itano N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers. 2014;6(3):1670–90.
61. Ganster RW, Taylor BS, Shao L, Geller DA. Complex regulation of human inducible nitric oxide synthase gene transcription by Stat 1 and NF-κB. Proc Natl Acad Sci U S A. 2001;98(15):8638–43.
62. Berraondo P, Sanmamed MF, Ochoa MC, Etxeberria I, Aznar MA, Pérez-Gracia JL, et al. Cytokines in clinical cancer immunotherapy. Br J Cancer. 2019;120(1):6–15.
63. Macy AM, Herrmann LM, Adams AC, Hastings KT. Major histocompatibility complex class II in the tumor microenvironment: functions of nonprofessional antigen-presenting cells. Curr Opin Immunol. 2023;83:102330.
64. Sedighzadeh SS, Khoshbin AP, Razi S, Keshavarz-Fathi M, Rezaei N. A narrative review of tumor-associated macrophages in lung cancer: regulation of macrophage polarization and therapeutic implications. Transl Lung Cancer Res. 2021;10(4):1889.
65. Wang H, Tian T, Zhang J. Tumor-associated macrophages (TAMs) in colorectal cancer (CRC): from mechanism to therapy and prognosis. Int J Mol Sci. 2021;22(16):8470.
66. Zhang M, He Y, Sun X, Li Q, Wang W, Zhao A, et al. A high M1/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients. J Ovarian Res. 2014;7:1–16.
67. Cao X, Li B, Chen J, Dang J, Chen S, Gunes EG, et al. Effect of cabazitaxel on macrophages improves CD47-targeted immunotherapy for triple-negative breast cancer. J ImmunoTherapy Cancer. 2021;9(3).
68. Fridlender ZG, Buchlis G, Kapoor V, Cheng G, Sun J, Singhal S, et al. CCL2 blockade augments cancer immunotherapy. Cancer Res. 2010;70(1):109–18.
69. Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014;74(18):5057–69.
70. Peranzoni E, Lemoine J, Vimeux L, Feuillet V, Barrin S, Kantari-Mimoun C, et al. Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti–PD-1 treatment. Proc Natl Acad Sci U S A. 2018;115(17):E4041–E50.
71. Kurte M, López M, Aguirre A, Escobar A, Aguillón JC, Charo J, et al. A synthetic peptide homologous to functional domain of human IL-10 down-regulates expression of MHC class I and Transporter associated with Antigen Processing 1/2 in human melanoma cells. J Immunol. 2004;173(3):1731–7.
72. Bak SP, Alonso A, Turk MJ, Berwin B. Murine ovarian cancer vascular leukocytes require arginase-1 activity for T cell suppression. Mol Immunol. 2008;46(2):258–68.
73. Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol. 2010;22(2):231–7.
74. Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limón P. The polarization of immune cells in the tumour environment by TGFβ. Nat Rev Immunol. 2010;10(8):554–67.
75. Ito M, Minamiya Y, Kawai H, Saito S, Saito H, Nakagawa T, et al. Tumor-derived TGFβ-1 induces dendritic cell apoptosis in the sentinel lymph node. J Immunol. 2006;176(9):5637–43.
76. Matsuda M, Salazar F, Petersson M, Masucci G, Hansson J, Pisa P, et al. Interleukin 10 pretreatment protects target cells from tumor-and allo-specific cytotoxic T cells and downregulates HLA class I expression. J Exp Med. 1994;180(6):2371–6.
77. Ben-Baruch A. Inflammation-associated immune suppression in cancer: the roles played by cytokines, chemokines and additional mediators. Semin Cancer Biol. 2006;16(1):38–52.
78. Beissert S, Hosoi J, Grabbe S, Asahina A, Granstein RD. IL-10 inhibits tumor antigen presentation by epidermal antigen-presenting cells. J Immunol. 1995;154(3):1280–6.
79. Sica A, Saccani A, Bottazzi B, Polentarutti N, Vecchi A, Damme JV, et al. Autocrine production of IL-10 mediates defective IL-12 production and NF-κB activation in tumor-associated macrophages. J Immunol. 2000;164(2):762–7.
80. Miotto D, Cascio NL, Stendardo M, Querzoli P, Pedriali M, De Rosa E, et al. CD8+ T cells expressing IL-10 are associated with a favourable prognosis in lung cancer. Lung Cancer. 2010;69(3):355–60.
81. Mocellin S, Marincola FM, Young HA. Interleukin-10 and the immune response against cancer: a counterpoint. J leukocyte Biol. 2005;78(5):1043–51.
82. Marigo I, Dolcetti L, Serafini P, Zanovello P, Bronte V. Tumor‐induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev. 2008;222(1):162–79.
83. Kusmartsev S, Nefedova Y, Yoder D, Gabrilovich DI. Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol. 2004;172(2):989–99.
84. Weihrauch D, Zimmermann R, Arras M, Schaper J. Expression of extracellular matrix proteins and the role of fibroblasts and macrophages in repair processes in ischemic porcine myocardium. Cell Mol Biol Res. 1994;40(2):105–16.
85. Felcht M, Luck R, Schering A, Seidel P, Srivastava K, Hu J, et al. Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling. J Clin Invest. 2012;122(6):1991–2005.
86. Falcone DJ, Khan KF, Layne T, Fernandes L. Macrophage formation of angiostatin during inflammation: a byproduct of the activation of plasminogen. J Biol Chemistry. 1998;273(47):31480–5.
87. Voronov E, Shouval DS, Krelin Y, Cagnano E, Benharroch D, Iwakura Y, et al. IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci U S A. 2003;100(5):2645–50.
88. Hammer T, Tritsaris K, Hübschmann MV, Gibson J, Nisato RE, Pepper MS, et al. IL-20 activates human lymphatic endothelial cells causing cell signalling and tube formation. Microvascular Res. 2009;78(1):25–32.
89. Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res. 2009;29(6):313–26.
90. Cursiefen C, Maruyama K, Bock F, Saban D, Sadrai Z, Lawler J, et al. Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes. J Exp Med. 2011;208(5):1083–92.
91. Onishi T, Nishizuka T, Kurahashi T, Arai T, Iwatsuki K, Yamamoto M, et al. Topical bFGF improves secondary lymphedema through lymphangiogenesis in a rat tail model. Plast Reconstr Surg Glob Open. 2014;2(8):e196.
92. Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, et al. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest. 2004;113(7):1040–50.
93. Sunderkötter C, Goebeler M, Schulze-Osthoff K, Bhardwaj R, Sorg C. Macrophage-derived angiogenesis factors. Pharmacol Ther. 1991;51(2):195–216.
94. Ferrari G, Cook BD, Terushkin V, Pintucci G, Mignatti P. Transforming growth factor‐beta 1 (TGF‐β1) induces angiogenesis through vascular endothelial growth factor (VEGF)‐mediated apoptosis. J Cell Physiol. 2009;219(2):449–58.
95. Guo C, Buranych A, Sarkar D, Fisher PB, Wang X-Y. The role of tumor-associated macrophages in tumor vascularization. Vascular cell. 2013;5:1–12.
96. Badawi MA, Abouelfadl DM, El-Sharkawy SL, Abd El-Aal WE, Abbas NF. Tumor-associated macrophage (TAM) and angiogenesis in human colon carcinoma. Open Access Maced J Med Sci. 2015;3(2):209.
97. Hwang I, Kim JW, Ylaya K, Chung EJ, Kitano H, Perry C, et al. Tumor-associated macrophage, angiogenesis and lymphangiogenesis markers predict prognosis of non-small cell lung cancer patients. J Translat Med. 2020;18:1–15.
98. Atanasov G, Pötner C, Aust G, Schierle K, Dietel C, Benzing C, et al. TIE2-expressing monocytes and M2-polarized macrophages impact survival and correlate with angiogenesis in adenocarcinoma of the pancreas. Oncotarget. 2018;9(51):29715.
99. Yang Y, Guo Z, Chen W, Wang X, Cao M, Han X, et al. M2 macrophage-derived exosomes promote angiogenesis and growth of pancreatic ductal adenocarcinoma by targeting E2F2. Mol Therapy. 2021;29(3):1226–38.
100. Wei K, Ma Z, Yang F, Zhao X, Jiang W, Pan C, et al. M2 macrophage-derived exosomes promote lung adenocarcinoma progression by delivering miR-942. Cancer lett. 2022;526:205–16.
101. Su P, Jiang L, Zhang Y, Yu T, Kang W, Liu Y, et al. Crosstalk between tumor-associated macrophages and tumor cells promotes chemoresistance via CXCL5/PI3K/AKT/mTOR pathway in gastric cancer. Cancer Cell Int. 2022;22(1):290.
102. Li D, Ji H, Niu X, Yin L, Wang Y, Gu Y, et al. Tumor‐associated macrophages secrete CC‐chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer. Cancer Sci. 2020;111(1):47–58.
103. Niu X, Ma J, Li J, Gu Y, Yin L, Wang Y, et al. Sodium/glucose cotransporter 1-dependent metabolic alterations induce tamoxifen resistance in breast cancer by promoting macrophage M2 polarization. Cell Death Dis. 2021;12(6):509.
104. Binenbaum Y, Fridman E, Yaari Z, Milman N, Schroeder A, Ben David G, et al. Transfer of miRNA in macrophage-derived exosomes induces drug resistance in pancreatic adenocarcinoma. Cancer Res. 2018;78(18):5287–99.
105. Kanlikilicer P, Bayraktar R, Denizli M, Rashed MH, Ivan C, Aslan B, et al. Corrigendum to 'Exosomal miRNA confers chemo resistance via targeting Cav1/p-gp/M2-type macrophage axis in ovarian cancer' [EBioMedicine 38 (2018) 100-112]. EBioMedicine. 2020;52:102630.
106. Sangaletti S, Di Carlo E, Gariboldi S, Miotti S, Cappetti B, Parenza M, et al. Macrophage-derived SPARC bridges tumor cell-extracellular matrix interactions toward metastasis. Cancer Res. 2008;68(21):9050–9.
107. Fu X-T, Dai Z, Song K, Zhang Z-J, Zhou Z-J, Zhou S-L, et al. Macrophage-secreted IL-8 induces epithelial-mesenchymal transition in hepatocellular carcinoma cells by activating the JAK2/STAT3/Snail pathway. Int J Oncol. 2014;46(2):587–96.
108. Lin EY, Li J-F, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA, et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 2006;66(23):11238–46.
109. Helm O, Held‐Feindt J, Grage‐Griebenow E, Reiling N, Ungefroren H, Vogel I, et al. Tumor‐associated macrophages exhibit pro‐and anti‐inflammatory properties by which they impact on pancreatic tumorigenesis. Int J Cancer. 2014;135(4):843–61.
110. Wyckoff JB, Wang Y, Lin EY, Li J-f, Goswami S, Stanley ER, et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 2007;67(6):2649–56.
111. DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, et al. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell. 2009;16(2):91–102.
112. Robinson BD, Sica GL, Liu YF, Rohan TE, Gertler FB, Condeelis JS, et al. Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination. Clin Cancer Res. 2009;15(7):2433–41.
113. Wang JJ, Wang Y, Liu Y, Yang R. SPP1+ macrophages in tumor immunosuppression: mechanisms and therapeutic implications. Front Immunol. 2025;Volume 16 - 2025.
114. Wang X, Wang Y, Yang L, Zhang Y, Yang L. TREM2+ macrophages: a key role in disease development. Front Immunol. 2025;Volume 16 - 2025.
115. Revel M, Sautès-Fridman C, Fridman W-H, Roumenina LT. C1q+ macrophages: passengers or drivers of cancer progression. Trends in Cancer. 2022;8(7):517–26.
116. Cui J, Zhang Y, Yang L. IFN-gamma in the tumor microenvironment: dual roles in cancer progression and therapy. Excli j. 2025;24:1352–71.
117. Nalio Ramos R, Missolo-Koussou Y, Gerber-Ferder Y, Bromley CP, Bugatti M, Núñez NG, et al. Tissue-resident FOLR2(+) macrophages associate with CD8(+) T cell infiltration in human breast cancer. Cell. 2022;185(7):1189–207.e25.
118. Xu X, Wu Z, Zeng Z, Cao J, Chen L. Integrating single-cell RNA sequencing data to decipher heterogeneity and function of macrophages in various organs and diseases. Clin Translat Discovery. 2024;4(5):e70005.
119. Palma A. The Landscape of SPP1 + Macrophages Across Tissues and Diseases: A Comprehensive Review. Immunology. 2025;176(2):179–96.
120. Guo Q, Qian Z-M. Macrophage based drug delivery: Key challenges and strategies. Bioactive Materials. 2024;38:55–72.
121. Chelliah R, Rubab M, Vijayalakshmi S, Karuvelan M, Barathikannan K, Oh D-H. Liposomes for drug delivery: Classification, therapeutic applications, and limitations. Next Nanotechnology. 2025;8:100209.
122. Danhier F. To exploit the tumor microenvironment: Since the EPR effect fails in the clinic, what is the future of nanomedicine? J Control Release. 2016;244:108–21.
123. Li R, He Y, Zhu Y, Jiang L, Zhang S, Qin J, et al. Route to rheumatoid arthritis by macrophage-derived microvesicle-coated nanoparticles. Nano lett. 2018;19(1):124–34.
124. Shi J, Kantoff PW, Wooster R, Farokhzad OC. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer. 2017;17(1):20–37.
125. Chen W, Schilperoort M, Cao Y, Shi J, Tabas I, Tao W. Macrophage-targeted nanomedicine for the diagnosis and treatment of atherosclerosis. Natu Rev Cardiol. 2022;19(4):228–49.
126. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41(1):14–20.
127. Van Overmeire E, Laoui D, Keirsse J, Van Ginderachter JA, Sarukhan A. Mechanisms driving macrophage diversity and specialization in distinct tumor microenvironments and parallelisms with other tissues. Front Immunol. 2014;5:127.
128. Coulis G, Jaime D, Guerrero-Juarez C, Kastenschmidt JM, Farahat PK, Nguyen Q, et al. Single-cell and spatial transcriptomics identify a macrophage population associated with skeletal muscle fibrosis. Sci Adv. 2023;9(27):eadd9984.
129. TingáZheng X, MingáLi C. Effect of particle shape on phagocytosis of CdTe quantum dot–cystine composites. Med Chem Comm. 2010;1(1):84–6.
130. Cao H, Dan Z, He X, Zhang Z, Yu H, Yin Q, et al. Liposomes coated with isolated macrophage membrane can target lung metastasis of breast cancer. ACS nano. 2016;10(8):7738–48.
131. Aderem A, Underhill DM. Mechanisms of phagocytosis in macrophages. Annu Rev Immunol. 1999;17(1):593–623.
132. Kumari S, Mg S, Mayor S. Endocytosis unplugged: multiple ways to enter the cell. Cell Res. 2010;20(3):256–75.
133. Adjei IM, Sharma B, Labhasetwar V. Nanoparticles: cellular uptake and cytotoxicity. Nanomaterial: impacts on cell biology and medicine. Adv Exp Med Biol. 2014:73–91.
134. Li S, Feng S, Ding L, Liu Y, Zhu Q, Qian Z, et al. Nanomedicine engulfed by macrophages for targeted tumor therapy. Int J Nanomedicine. 2016:4107–24.
135. Qiang L, Cai Z, Jiang W, Liu J, Tai Z, Li G, et al. A novel macrophage-mediated biomimetic delivery system with NIR-triggered release for prostate cancer therapy. J Nanobiotechnol. 2019;17:1–15.
136. Nguyen VD, Min H-K, Kim D-H, Kim C-S, Han J, Park J-O, et al. Macrophage-mediated delivery of multifunctional nanotherapeutics for synergistic chemo–photothermal therapy of solid tumors. ACS Appl Mater Interfaces. 2020;12(9):10130–41.
137. Xue F, Zhu S, Tian Q, Qin R, Wang Z, Huang G, et al. Macrophage-mediated delivery of magnetic nanoparticles for enhanced magnetic resonance imaging and magnetothermal therapy of solid tumors. J Colloid Interface Sci. 2023;629:554–62.
138. Choi J, Kim H-Y, Ju EJ, Jung J, Park J, Chung H-K, et al. Use of macrophages to deliver therapeutic and imaging contrast agents to tumors. Biomaterials. 2012;33(16):4195–203.
139. Chen C, Zhang Y, Chen Z, Yang H, Gu Z. Cellular transformers for targeted therapy. Adv Drug Deliv Rev. 2021;179:114032.
140. Stephan MT, Moon JJ, Um SH, Bershteyn A, Irvine DJ. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat Med. 2010;16(9):1035–41.
141. Kuerban K, Gao X, Zhang H, Liu J, Dong M, Wu L, et al. Doxorubicin-loaded bacterial outer-membrane vesicles exert enhanced anti-tumor efficacy in non-small-cell lung cancer. Acta Pharm Sin B. 2020;10(8):1534–48.
142. Huang Y, Guan Z, Dai X, Shen Y, Wei Q, Ren L, et al. Engineered macrophages as near-infrared light activated drug vectors for chemo-photodynamic therapy of primary and bone metastatic breast cancer. Nat Commun. 2021;12(1):4310.
143. Sakai H, Kokura S, Ishikawa T, Tsuchiya R, Okajima M, Matsuyama T, et al. Effects of anticancer agents on cell viability, proliferative activity and cytokine production of peripheral blood mononuclear cells. J Clin Biochem Nutr. 2013;52(1):64–71.
144. Xiao Q, Li X, Li Y, Wu Z, Xu C, Chen Z, et al. Biological drug and drug delivery-mediated immunotherapy. Acta Pharmaceutica Sinica B. 2021;11(4):941–60.
145. Hou AJ, Chen LC, Chen YY. Navigating CAR-T cells through the solid-tumour microenvironment. Nat Rev Drug Discov. 2021;20(7):531–50.
146. Luo H, Ding Y, Zhao X. Preclinical and clinical studies on CAR-NK cell therapy: latest update from 2025 ASH Annual Meeting. Exp Hemato Oncol. 2026;15(1):46.
147. Asmamaw Dejenie T, Tiruneh G/Medhin M, Dessie Terefe G, Tadele Admasu F, Wale Tesega W, Chekol Abebe E. Current updates on generations, approvals, and clinical trials of CAR T-cell therapy. Hum Vaccin Immunother. 2022;18(6):2114254.
148. Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ. Toxicity and management in CAR T-cell therapy. Mol Ther Oncol. 2016;3.
149. Klichinsky M, Ruella M, Shestova O, Lu XM, Best A, Zeeman M, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol. 2020;38(8):947–53.
150. Klichinsky M, Ruella M, Shestova O, Lu XM, Best A, Zeeman M, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol. 2020;38(8):947–53.
151. Kashfi K, Kannikal J, Nath N. Macrophage reprogramming and cancer therapeutics: role of iNOS-derived NO. Cells. 2021;10(11):3194.
152. Zhang L, Tian L, Dai X, Yu H, Wang J, Lei A, et al. Pluripotent stem cell-derived CAR-macrophage cells with antigen-dependent anti-cancer cell functions. J Hematol Oncol. 2020;13:1–5.
153. Eisenberg S, Powers A, Lohmueller J, Luketich J, Dhupar R, Soloff A. 112 Tumor-specific reactivity and effector function of chimeric antigen receptor engineered macrophages targeting MUC1. J Immunol Ther Cancer. 2021;9(Suppl 2):A122–A.
154. Annunziata C, Dansky-Ullmann C, Ghobadi A, Weng D, Vanas J, Ekwede I, et al. 1308TiP - A phase I study of intraperitoneal MCY-M11 Anti-mesothelin CAR for women with platinum resistant high grade serous adenocarcinoma of the ovary, primary peritoneum, or fallopian tube, or subjects with peritoneal mesothelioma with recurrence after prior chemotherapy. Ann Oncol. 2019;30:v531.
155. Reiss K, Yuan Y, Ueno N, Johnson M, Claire Dees E, Angelos M, et al. 634 A phase 1, first-in-human (FIH) clinical trial of the anti-HER2 CAR macrophage CT-0508 in participants with HER2 overexpressing solid tumors. Journal for ImmunoTherapy of Cancer. 2022;10(Suppl 2):A665–A.
156. Alrehaili M, Couto PS, Khalife R, Rafiq QA. CAR-macrophages in solid tumors: promise, progress, and prospects. NPJ Precis Oncol. 2025;9(1):382.
157. Li J, Chen P, Ma W. The next frontier in immunotherapy: potential and challenges of CAR-macrophages. Exp Hematol Oncol. 2024;13(1):76.
158. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. New Eng J Med. 2021;384(5):403–16.
159. Bertrand N, Wu J, Xu X, Kamaly N, Farokhzad OC. Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv Drug Deliv Rev. 2014;66:2–25.
160. Wang H, Wu J, Williams GR, Fan Q, Niu S, Wu J, et al. Platelet-membrane-biomimetic nanoparticles for targeted antitumor drug delivery. J Nanobiotechnol. 2019;17:1–16.
161. Vijayan V, Uthaman S, Park I-K. Cell membrane-camouflaged nanoparticles: a promising biomimetic strategy for cancer theragnostics. Polymers. 2018;10(9):983.
162. Rao L, Zhao SK, Wen C, Tian R, Lin L, Cai B, et al. Activating macrophage‐mediated cancer immunotherapy by genetically edited nanoparticles. Adv Mat. 2020;32(47):2004853.
163. Gong C, Yu X, You B, Wu Y, Wang R, Han L, et al. Macrophage-cancer hybrid membrane-coated nanoparticles for targeting lung metastasis in breast cancer therapy. J Nanobiotechnol. 2020;18:1–17.
164. Wu Y, Wan S, Yang S, Hu H, Zhang C, Lai J, et al. Macrophage cell membrane-based nanoparticles: a new promising biomimetic platform for targeted delivery and treatment. Journal of Nanobiotechnology. 2022;20(1):542.
165. Wu Y, Wan S, Yang S, Hu H, Zhang C, Lai J, et al. Macrophage cell membrane-based nanoparticles: a new promising biomimetic platform for targeted delivery and treatment. J Nanobiotechnol. 2022;20(1):542.
166. Zhang Y, Cai K, Li C, Guo Q, Chen Q, He X, et al. Macrophage-membrane-coated nanoparticles for tumor-targeted chemotherapy. Nano lett. 2018;18(3):1908–15.
167. Sun K, Yu W, Ji B, Chen C, Yang H, Du Y, et al. Saikosaponin D loaded macrophage membrane-biomimetic nanoparticles target angiogenic signaling for breast cancer therapy. Applied Materials Today. 2020;18:100505.
168. Parodi A, Quattrocchi N, Van De Ven AL, Chiappini C, Evangelopoulos M, Martinez JO, et al. Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions. Nat Nanotechnol. 2013;8(1):61–8.
169. Cao X, Tan T, Zhu D, Yu H, Liu Y, Zhou H, et al. Paclitaxel-loaded macrophage membrane camouflaged albumin nanoparticles for targeted cancer therapy. Int J Nanomed. 2020:1915–28.
170. Xuan M, Shao J, Dai L, Li J, He Q. Macrophage cell membrane camouflaged Au nanoshells for in vivo prolonged circulation life and enhanced cancer photothermal therapy. ACS Appl Mater Interfaces. 2016;8(15):9610–8.
171. Maisano D, Mimmi S, Dattilo V, Marino F, Gentile M, Vecchio E, et al. A novel phage display based platform for exosome diversity characterization. Nanoscale. 2022;14(8):2998–3003.
172. Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7(1):1535750.
173. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478):eaau6977.
174. Brennan K, Martin K, FitzGerald SP, O’Sullivan J, Wu Y, Blanco A, et al. A comparison of methods for the isolation and separation of extracellular vesicles from protein and lipid particles in human serum. Sci Rep. 2020;10(1):1039.
175. Kim J, Hwang YH, Nam G-H, Kim I-S. Breaking barriers: Engineering extracellular vesicles for enhanced endosomal escape and therapeutic delivery. J Control Release. 2026;389:114462.
176. Bader J, Brigger F, Leroux J-C. Extracellular vesicles versus lipid nanoparticles for the delivery of nucleic acids. Adv Drug Deliv Rev. 2024;215:115461.
177. Veerman RE, Akpinar GG, Eldh M, Gabrielsson S. Immune cell-derived extracellular vesicles–functions and therapeutic applications. Trends Mol Med. 2019;25(5):382–94.
178. Haney MJ, Zhao Y, Jin YS, Li SM, Bago JR, Klyachko NL, et al. Macrophage-Derived Extracellular Vesicles as Drug Delivery Systems for Triple Negative Breast Cancer (TNBC) Therapy. J Neuroimmune Pharmacol. 2020;15(3):487–500.
179. Kim MS, Haney MJ, Zhao Y, Mahajan V, Deygen I, Klyachko NL, et al. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine. 2016;12(3):655–64.
180. Wang P, Wang H, Huang Q, Peng C, Yao L, Chen H, et al. Exosomes from M1-Polarized Macrophages Enhance Paclitaxel Antitumor Activity by Activating Macrophages-Mediated Inflammation. Theranostics. 2019;9(6):1714–27.
181. Zhao Y, Zheng Y, Zhu Y, Zhang Y, Zhu H, Liu T. M1 Macrophage-Derived Exosomes Loaded with Gemcitabine and Deferasirox against Chemoresistant Pancreatic Cancer. Pharmaceutics. 2021;13(9).
182. Deci MB, Ferguson SW, Scatigno SL, Nguyen J. Modulating macrophage polarization through CCR2 inhibition and multivalent engagement. Mol Pharmaceutics. 2018;15(7):2721–31.
183. Bonapace L, Coissieux M-M, Wyckoff J, Mertz KD, Varga Z, Junt T, et al. Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature. 2014;515(7525):130–3.
184. Fujiwara T, Yakoub MA, Chandler A, Christ AB, Yang G, Ouerfelli O, et al. CSF1/CSF1R signaling inhibitor pexidartinib (PLX3397) reprograms tumor-associated macrophages and stimulates T-cell infiltration in the sarcoma microenvironment. Mol Cancer Therapeutics. 2021;20(8):1388–99.
185. Sluijter M, van der Sluis TC, van der Velden PA, Versluis M, West BL, van der Burg SH, et al. Inhibition of CSF-1R supports T-cell mediated melanoma therapy. PloS one. 2014;9(8):e104230.
186. Atzori MG, Ceci C, Ruffini F, Trapani M, Barbaccia ML, Tentori L, et al. Role of VEGFR‐1 in melanoma acquired resistance to the BRAF inhibitor vemurafenib. J Cel Mol Med. 2020;24(1):465–75.
187. Huang Z, Gan J, Long Z, Guo G, Shi X, Wang C, et al. Targeted delivery of let-7b to reprogramme tumor-associated macrophages and tumor infiltrating dendritic cells for tumor rejection. Biomaterials. 2016;90:72–84.
188. Dahal LN, Dou L, Hussain K, Liu R, Earley A, Cox KL, et al. STING activation reverses lymphoma-mediated resistance to antibody immunotherapy. Cancer Res. 2017;77(13):3619–31.
189. Wu L, Zhang X, Zheng L, Zhao H, Yan G, Zhang Q, et al. RIPK3 orchestrates fatty acid metabolism in tumor-associated macrophages and hepatocarcinogenesis. Cancer Immunol Res. 2020;8(5):710–21.
190. Shan H, Dou W, Zhang Y, Qi M. Targeted ferritin nanoparticle encapsulating CpG oligodeoxynucleotides induces tumor-associated macrophage M2 phenotype polarization into M1 phenotype and inhibits tumor growth. Nanoscale. 2020;12(43):22268–80.
191. Galipeau J, Sensébé L. Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities. Cell Stem Cell. 2018;22(6):824–33.
192. Abou-El-Enein M, Elsallab M, Feldman SA, Fesnak AD, Heslop HE, Marks P, et al. Scalable Manufacturing of CAR T cells for Cancer Immunotherapy. Blood Cancer Discov. 2021;2(5):408–22.
193. Owens AP, Mackman N, Weber C, Mause S. Microparticles in Hemostasis and Thrombosis. Circul Res. 2011;108(10):1284–97.
194. van der Meel R, Fens MHAM, Vader P, van Solinge WW, Eniola-Adefeso O, Schiffelers RM. Extracellular vesicles as drug delivery systems: Lessons from the liposome field. J Control Release. 2014;195:72–85.
195. Wiklander OPB, Nordin JZ, O'Loughlin A, Gustafsson Y, Corso G, Mäger I, et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles. 2015;4(1):26316.
196. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478):eaau6977.
197. Witwer KW, Théry C. Extracellular vesicles or exosomes? On primacy, precision, and popularity influencing a choice of nomenclature. J Extracell Vesicles. 2019;8(1):1648167.
198. Lu S, Cui Q, Zheng H, Ma Y, Kang Y, Tang K. Challenges and Opportunities for Extracellular Vesicles in Clinical Oncology Therapy. Bioengineering (Basel). 2023;10(3).
199. Klichinsky M, Ruella M, Shestova O, Lu XM, Best A, Zeeman M, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol. 2020;38(8):947–53.
Files
IssueArticles in Press QRcode
SectionReview Article(s)
Keywords
Macrophages; Cancer; Immunotherapy; Antitumor activity; Protumor activity

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Hajisharifi K, Emadi S, Aghamollaei H, Ghalavand M. Engineering and Targeting Macrophages for Cancer Therapy. Iran J Allergy Asthma Immunol. 2026;:1-29.