Les Liaisons dangereuses: the paradoxical outcomes of the cytotoxic activity of tumor macrophages

The study of the role of the immune system in tumor progression has been ongoing for over a century, starting with Paul Ehrlich’s hypothesis on its role in limiting the development of oncological diseases. The development of cancer immunology has confirmed this concept and identified mechanisms of complex interactions between immune system cells and both foreign agents and transformed cells within the organism. Macrophages, natural killers, and T-lymphocytes play key roles in destroying tumor cells. Among them, special attention is given to tumor-associated macrophages. Tumor cells can modulate macrophage activity, transforming them into cells with immunosuppressive properties that promote angiogenesis and extracellular matrix remodeling. As a result, the largest population of tumor-associated macrophages consists of cells with an anti-inflammatory/pro-tumor phenotype (M2).
Macrophages with an anti-inflammatory phenotype (M1) are characterized by the production of pro-inflammatory cytokines, reactive oxygen species, and strong cytotoxic activity. They can directly or indirectly destroy tumor cells by involving other immune cells. Traditionally, the cytotoxic activity of macrophages is considered an important mechanism in limiting tumor growth, but in some cases, it is insufficient for effective tumor control. Recent data suggest that tumor cells can develop defense mechanisms against macrophage cytotoxicity and acquire the ability to overcome it. Moreover, tumor cells resulting from interaction with cytotoxic macrophages possess other properties that provide growth advantages.
This review is dedicated to describing a new pro-tumor function of M1 macrophages, traditionally considered anti-tumor.

1. Liu C., Yang M., Zhang D. et al. Clinical cancer immunotherapy: current progress and prospects. Front Immunol 2022;13:961805. DOI: 10.3389/fimmu.2022.961805

2. Wang S., Xie K., Liu T. Cancer immunotherapies: from efficacy to resistance mechanisms – not only checkpoint matters. Front Immunol 2021;12:690112. DOI: 10.3389/fimmu.2021.690112

3. Murciano-Goroff Y.R., Warner A.B., Wolchok J.D. The future of cancer immunotherapy: microenvironment-targeting combinations. Cell Res 2020;30(6):507–19. DOI: 10.1038/s41422-020-0337-2

4. Wang Q., Shao X., Zhang Y. et al. Role of tumor microenvironment in cancer progression and therapeutic strategy. Cancer Med 2023;12(10):11149–65. DOI: 10.1002/cam4.5698

5. Franklin R.A., Li M.O. Ontogeny of tumor-associated macrophages and its implication in cancer regulation. Trends Cancer 2016;2 (1):20–34. DOI: 10.1016/j.trecan.2015.11.004

6. Mantovani A., Allavena P., Marchesi F., Garlanda C. Macrophages as tools and targets in cancer therapy. Nat Rev Drug Discov 2022;21(11):799–820. DOI: 10.1038/s41573-022-00520-5

7. Shapouri-Moghaddam A., Mohammadian S., Vazini H. et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol 2018;233(9):6425–40. DOI: 10.1002/jcp.26429

8. Locati M., Curtale G., Mantovani A. Diversity, mechanisms, and significance of macrophage plasticity. Ann Rev Pathol 2020;15:123–47. DOI: 10.1146/annurev-pathmechdis-012418-012718

9. Yunna C., Mengru H., Lei W., Weidong C. Macrophage M1/M2 polarization. Eur J Pharmacol 2020;877:173090. DOI: 10.1016/j.ejphar.2020.173090

10. Chen S., Saeed A., Liu Q. et al. Macrophages in immunoregulation and therapeutics. Signal Transduct Target Ther 2023;8(1):207. DOI: 10.1038/s41392-023-01452-1

11. Gratchev A., Kzhyshkowska J., Kothe K. et al. Mphi1 and Mphi2 can be re-polarized by Th2 or Th1 cytokines, respectively, and respond to exogenous danger signals. Immunobiology 2006;211(6–8):473–86. DOI: 10.1016/j.imbio.2006.05.017

12. Roszer T. Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediators Inflamm 2015;2015:816460. DOI: 10.1155/2015/816460

13. Gratchev A., Kzhyshkowska J., Utikal J., Goerdt S. Interleukin-4 and dexamethasone counterregulate extracellular matrix remodelling and phagocytosis in type-2 macrophages. Scand J Immunol 2005;61(1):10–7. DOI: 10.1111/j.0300-9475.2005.01524.x

14. Mantovani A., Sica A., Sozzani S. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 2004;25(12):677–86.

15. Strizova Z., Benesova I., Bartolini R. et al. M1/M2 macrophages and their overlaps – myth or reality? Clin Sci (Lond) 2023;137(15):1067–93. DOI: 10.1042/CS20220531

16. Boutilier A.J., Elsawa S.F. Macrophage polarization states in the tumor microenvironment. Int J Mol Sci 2021;22(13):6995. DOI: 10.3390/ijms22136995

17. Lai Y.S., Wahyuningtyas R., Aui S.P., Chang K.T. Autocrine VEGF signalling on M2 macrophages regulates PD-L1 expression for immunomodulation of T cells. J Cell Mol Med 2019;23(2):1257–67. DOI: 10.1111/jcmm.14027

18. Jones C.V., Ricardo S.D. Macrophages and CSF-1: implications for development and beyond. Organogenesis 2013;9(4):249–60. DOI: 10.4161/org.25676

19. Kratochvill F., Neale G., Haverkamp J.M. et al. TNF counterbalances the emergence of M2 tumor macrophages. Cell Rep 2015;12 (11):1902–14. DOI: 10.1016/j.celrep.2015.08.033

20. Li W., Wu F., Zhao S. et al. Correlation between PD-1/PD-L1 expression and polarization in tumor-associated macrophages: a key player in tumor immunotherapy. Cytokine Growth Factor Rev 2022;67:49–57. DOI: 10.1016/j.cytogfr.2022.07.004

21. Zajac E., Schweighofer B., Kupriyanova T.A. et al. Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9. Blood 2013;122(25):4054–67. DOI: 10.1182/blood-2013-05-501494

22. Kerneur C., Cano C.E., Olive D. Major pathways involved in macrophage polarization in cancer. Front Immunol 2022;13:1026954. DOI: 10.3389/fimmu.2022.1026954

23. Chen W., Chen M., Hong L. et al. M2-like tumor-associated macrophage-secreted CCL2 facilitates gallbladder cancer stemness and metastasis. Exp Hematol Oncol 2024;13(1):83. DOI: 10.1186/s40164-024-00550-2

24. Jiang X., Wang J., Lin L. et al. Macrophages promote pre-metastatic niche formation of breast cancer through aryl hydrocarbon receptor activity. Signal Transduct Target Ther 2024;9(1):352. DOI: 10.1038/s41392-024-02042-5

25. Wang Y., Jia J., Wang F. et al. Pre-metastatic niche: formation, characteristics and therapeutic implication. Signal Transduct Target Ther 2024;9(1):236. DOI: 10.1038/s41392-024-01937-7

26. Xu Y., Wang X., Liu L. et al. Role of macrophages in tumor progression and therapy (review). Int J Oncol 2022;60(5):57. DOI: 10.3892/ijo.2022.5347

27. Yi B., Cheng Y., Chang R. et al. Prognostic significance of tumorassociated macrophages polarization markers in lung cancer: a pooled analysis of 5105 patients. Biosci Rep 2023;43(2):BSR20221659. DOI: 10.1042/BSR20221659

28. Troiano G., Caponio V.C.A., Adipietro I. et al. Prognostic significance of CD68(+) and CD163(+) tumor associated macrophages in head and neck squamous cell carcinoma: a systematic review and meta-analysis. Oral Oncol 2019;93:66–75. DOI: 10.1016/j.oraloncology.2019.04.019

29. Cortese N., Carriero R., Laghi L. et al. Prognostic significance of tumor-associated macrophages: past, present and future. Seminars Immunol 2020;48:101408. DOI: 10.1016/j.smim.2020.101408

30. Allison E., Edirimanne S., Matthews J., Fuller S.J. Breast cancer survival outcomes and tumor-associated macrophage markers: a systematic review and meta-analysis. Oncol Ther 2023;11(1):27–48. DOI: 10.1007/s40487-022-00214-3

31. Yuan X., Zhang J., Li D. et al. Prognostic significance of tumorassociated macrophages in ovarian cancer: a meta-analysis. Gynecol Oncol 2017;147(1):181–7. DOI: 10.1016/j.ygyno.2017.07.007

32. Harjes U. Educating macrophages in melanoma. Nat Rev Cancer 2021;21(1):4. DOI: 10.1038/s41568-020-00317-x

33. Qi D., Lu Y., Qu H. et al. Independent prognostic value of CLDN6 in bladder cancer based on M2 macrophages related signature. iScience 2024;27(3):109138. DOI: 10.1016/j.isci.2024.109138

34. Yang G., Zhang L., Liu M. et al. CD163+ macrophages predict a poor prognosis in patients with primary T1 high-grade urothelial carcinoma of the bladder. World J Urol 2019;37(12):2721–6. DOI: 10.1007/s00345-018-02618-1

35. Montemurro N., Pahwa B., Tayal A. et al. Macrophages in recurrent glioblastoma as a prognostic factor in the synergistic system of the tumor microenvironment. Neurol Int 2023;15(2):595–608. DOI: 10.3390/neurolint15020037

36. Kovaleva O.V., Gratchev A.N., Makarova E.I. et al. Prognostic significance of sPD-1/sPD-L1 in renal cancer depending on the phenotype of tumor and stromal cells. Onkourologiya = Cancer Urology 2022;18(2):17–28. (In Russ.). DOI: 10.17650/1726-9776-2022-18-2-17–28

37. Kovaleva O.V., Podlesnaya P., Sorokin M. et al. Macrophage phenotype in combination with tumor microbiome composition predicts RCC patients’ survival: a pilot study. Biomedicines 2022;10(7):1516. DOI: 10.3390/biomedicines10071516

38. Abdulzhaliev A.T., Bulycheva I.V., Kovaleva O.V. et al. Expression of PD-L1 and PU.1 in malignant tumors from the membranes of peripheral nerves. Klinicheskaya i eksperimental’naya morfologiya = Clinical and Experimental Morphology 2023;12(2). (In Russ.). DOI: 10.31088/CEM2023.12.2.44-53

39. Khan S.U., Khan M.U., Azhar Ud Din M. et al. Reprogramming tumor-associated macrophages as a unique approach to target tumor immunotherapy. Front Immunol 2023;14:1166487. DOI: 10.3389/fimmu.2023.1166487

40. Li M., Jiang P., Wei S. et al. The role of macrophages-mediated communications among cell compositions of tumor microenvironment in cancer progression. Front Immunol 2023;14:1113312. DOI: 10.3389/fimmu.2023.1113312

41. Wang L.X., Zhang S.X., Wu H.J. et al. M2b macrophage polarization and its roles in diseases. J Leukoc Biol 2019;106(2):345–58. DOI: 10.1002/JLB.3RU1018-378RR

42. Martin-Manso G., Galli S., Ridnour L.A. et al. Thrombospondin 1 promotes tumor macrophage recruitment and enhances tumor cell cytotoxicity of differentiated U937 cells. Cancer Res 2008;68(17):7090–9. DOI: 10.1158/0008-5472.CAN-08-0643

43. Shikanai S., Yamada N., Yanagawa N. et al. Prognostic impact of tumor-associated macrophage-related markers in patients with adenocarcinoma of the lung. Ann Surg Oncol 2023;30(12):7527–37. DOI: 10.1245/s10434-023-13384-9

44. Li J., Li L., Li Y. et al. Tumor-associated macrophage infiltration and prognosis in colorectal cancer: systematic review and meta-analysis. Int J Colorectal Dis 2020;35(7):1203–10. DOI: 10.1007/s00384-020-03593-z

45. Kovaleva O.V., Rashidova M.A., Samoilova D.V. et al. Immunosuppressive phenotype of esophagus tumors stroma. Anal Cell Pathol (Amst) 2020;2020:5424780. DOI: 10.1155/2020/5424780

46. El-Zayat S.R., Sibaii H., Mannaa F.A. Toll-like receptors activation, signaling, and targeting: an overview. Bull Natl Res Cent 2019;43(1):187. DOI: 10.1186/s42269-019-0227-2

47. Wang N., Liang H., Zen K. Molecular mechanisms that influence the macrophage m1-m2 polarization balance. Front Immunol 2014;5:614. DOI: 10.3389/fimmu.2014.00614

48. Zhao X., Zhao J., Li D. et al. Akkermansia muciniphila: a potential target and pending issues for oncotherapy. Pharm Res 2023;196:106916. DOI: 10.1016/j.phrs.2023.106916

49. Xu S., Xiong Y., Fu B. et al. Bacteria and macrophages in the tumor microenvironment. Front Microbiol 2023;14:1115556. DOI: 10.3389/fmicb.2023.1115556

50. Zhou D., Li Y. Gut microbiota and tumor-associated macrophages: potential in tumor diagnosis and treatment. Gut Microbes 2023;15(2):2276314. DOI: 10.1080/19490976.2023.2276314

51. Albina J.E., Reichner J.S. Role of nitric oxide in mediation of macrophage cytotoxicity and apoptosis. Cancer Metastasis Rev 1998;17(1):39–53. DOI: 10.1023/a:1005904704618

52. De Groot J.W., De Weger R.A., Vandebriel R.J., Den Otter W. Differences in the induction of macrophage cytotoxicity by the specific T lymphocyte factor, specific macrophage arming factor (SMAF), and the lymphokine, macrophage activating factor (MAF). Immunobiology 1989;179(2–3):131–44. DOI: 10.1016/s0171-2985(89)80012-9

53. Reis E.S., Mastellos D.C., Ricklin D. et al. Complement in cancer: untangling an intricate relationship. Nat Rev Immunol 2018;18(1):5–18. DOI: 10.1038/nri.2017.97

54. Watkins S.K., Li B., Richardson K.S. et al. Rapid release of cytoplasmic IL-15 from tumor-associated macrophages is an initial and critical event in IL-12-initiated tumor regression. Eur J Immunol 2009;39(8):2126–35. DOI: 10.1002/eji.200839010

55. Weiskopf K., Weissman I.L. Macrophages are critical effectors of antibody therapies for cancer. MAbs 2015;7(2):303–10. DOI: 10.1080/19420862.2015.1011450

56. Gogesch P., Dudek S., van Zandbergen G. et al. The role of Fcreceptors on the effectiveness of therapeutic monoclonal antibodies. Int J Mol Sci 2021;22(16):8947. DOI: 10.3390/ijms22168947

57. Hubert P., Amigorena S. Antibody-dependent cell cytotoxicity in monoclonal antibody-mediated tumor immunotherapy. Oncoimmunology 2012;1(1):103–5. DOI: 10.4161/onci.1.1.17963

58. Zahavi D., AlDeghaither D., O’Connell A., Weiner L.M. Enhancing antibody-dependent cell-mediated cytotoxicity: a strategy for improving antibody-based immunotherapy. Antib Ther 2018;1(1):7–12. DOI: 10.1093/abt/tby002

59. Zhang X., Mosser D.M. Macrophage activation by endogenous danger signals. J Pathol 2008;214(2):161–78. DOI: 10.1002/path.2284

60. Munn D.H., Shafizadeh E., Attwood J.T. et al. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med 1999;189(9):1363–72. DOI: 10.1084/jem.189.9.1363

61. Meireson A., Devos M., Brochez L. IDO expression in cancer: different compartment, different functionality? Front Immunol 2020;11:531491. DOI: 10.3389/fimmu.2020.531491

62. Wang X., Lin Y. Tumor necrosis factor and cancer, buddies or foes? Acta Pharmacol Sin 2008;29(11):1275–88. DOI: 10.1111/j.1745-7254.2008.00889.x

63. Das A., Monteiro M., Barai A. et al. MMP proteolytic activity regulates cancer invasiveness by modulating integrins. Sci Rep 2017;7(1):14219. DOI: 10.1038/s41598-017-14340-w

64. El-Kenawi A., Ruffell B. Inflammation, ROS, and mutagenesis. Cancer Cell 2017;32(6):727–9. DOI: 10.1016/j.ccell.2017.11.015

65. Liu J., Geng X., Hou J., Wu G. New insights into M1/M2 macrophages: key modulators in cancer progression. Cancer Cell Int 2021;21(1):389. DOI: 10.1186/s12935-021-02089-2

66. Podlesnaya P.A., Kovaleva O.V., Petrenko A.A., Gratchev A.N. Cytotoxic activity of macrophages as a tumor malignancy factor. Bull Exp Biol Med 2022;174(1):147–51. DOI: 10.1007/s10517-022-05664-3

67. Kovaleva O.V., Podlesnaya P.A., Vasileva M.V. et al. Transcriptome of lung cancer cells resistant to the cytotoxic activity of macrophages. Dokl Biochem Biophys 2022;507(1):312–7. DOI: 10.1134/S160767292205009X

68. Kainulainen K., Takabe P., Heikkinen S. et al. M1 Macrophages induce protumor inflammation in melanoma cells through TNFR-NFkappaB signaling. J Investig Dermatol 2022;142(11):3041–51e10. DOI: 10.1016/j.jid.2022.04.024

69. Sharen G., Cheng H., Hu X. et al. M1-like tumor-associated macrophages enhance proliferation and anti-apoptotic ability of liver cancer cells via activating the NF-kappaB signaling pathway. Mol Med Rep 2022;26(5):331. DOI: 10.3892/mmr.2022.12847

70. Zhou Y., Xia L., Liu Q. et al. Induction of pro-inflammatory response via activated macrophage-mediated NF-kappaB and STAT3 pathways in gastric cancer cells. Cell Physiol Biochem 2018;47(4):1399–410. DOI: 10.1159/000490829

71. Lv C., Li S., Zhao J. et al. M1 macrophages enhance survival and invasion of oral squamous cell carcinoma by inducing GDF15-mediated ErbB2 phosphorylation. ACS Omega 2022;7(13):11405–14. DOI: 10.1021/acsomega.2c00571