Множественные аспекты влияния противоопухолевой химиотерапии на иммунный ответ

Химиотерапия злокачественных новообразований направлена на подавление процессов роста и пролиферации опухолевых клеток и является неотъемлемой частью лечения онкологических больных. Наряду с высокой противоопухолевой активностью, цитотоксическое действие химиопрепаратов распространяется и на иммунные клетки, приводя к панцитопении и, как следствие, к ослаблению иммунного ответа. Тем не менее действие химиотерапии на иммунную систему носит комплексный характер, поскольку одновременно с супрессивным влиянием вызывает стимуляцию противоопухолевой активности лимфоидных и миелоидных популяций.
Представленный обзор посвящен анализу и обобщению современных данных о влиянии химиотерапевтических препаратов, применяемых в стандартных схемах противоопухолевой терапии, на функционирование иммунной системы. Рассмотрены супрессорные механизмы действия химиотерапии, включая развитие цитопении. Особое внимание уделено анализу данных о модуляции противоопухолевого иммунного ответа в зависимости от группы химиотерапевтического препарата. Описаны механизмы усиления иммунного распознавания и стимуляции иммунных клеток в ответ на увеличение экспрессии опухолевых антигенов. Представлены сведения о влиянии химиотерапии на опухолевое микроокружение, включая перепрограммирование иммуносупрессорного профиля и активацию эффекторов иммунитета. Обобщенные данные указывают на разнонаправленное воздействие химиотерапии на состояние иммунной системы и ее влияние на формирование противоопухолевого иммунного ответа.

1. Anand U., Dey A., Chandel A.K.S. et al. Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics. Genes Dis 2023;10(4):1367–401. DOI: 10.1016/j.gendis.2022.02.007

2. Albert A. Chemotherapy: history and principles. In: Selective toxicity: the physico-chemical basis of therapy. Ed. by A. Albert. Dordrecht: Springer Netherlands, 1985. Pp. 206–265.

3. Morrison W.B. Cancer chemotherapy: an annotated history. J Vet Intern Med 2010;24(6):1249–62. DOI: 10.1111/j.1939-1676.2010.0590.x

4. Sharma A., Jasrotia S., Kumar A. Effects of chemotherapy on the immune system: implications for cancer treatment and patient outcomes. Naunyn Schmiedebergs Arch Pharmacol 2024;397(5):2551–66. DOI: 10.1007/s00210-023-02781-2

5. Vorontsova A., Kan T., Raviv Z. et al. The dichotomous role of bone marrow derived cells in the chemotherapy-treated tumor microenvironment. J Clin Med 2020;9(12):3912. DOI: 10.3390/jcm9123912

6. Galsky M.D., Guan X., Rishipathak D. et al. Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatinbased chemotherapy plus atezolizumab in urothelial cancer. Cell Rep Med 2024;5(2):101393. DOI: 10.1016/j.xcrm.2024.101393

7. Mukherjee O., Rakshit S., Shanmugam G. et al. Role of chemotherapeutic drugs in immunomodulation of cancer. Curr Res Immunol 2023;4:100068. DOI: 10.1016/j.crimmu.2023.100068

8. Galluzzi L., Humeau J., Buqué A. et al. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol 2020;17(12):725–41. DOI: 10.1038/s41571-020-0413-z

9. Shin D.S., Ribas A. The evolution of checkpoint blockade as a cancer therapy: what's here, what's next? Curr Opin Immunol 2015;33:23–35. DOI: 10.1016/j.coi.2015.01.006

10. Burnet M. Cancer – a biological approach. I. The processes of control. II. The Significance of somatic mutation 1957;1(5022):779–86. DOI: 10.1136/bmj.1.5022.779

11. Burnet F.M. The concept of immunological surveillance. Prog Exp Tumor Res 1970;13(1):1–27. DOI: 10.1159/000386035

12. Vesely M.D., Schreiber R.D. Cancer immunoediting: antigens, mechanisms, and implications to cancer immunotherapy. Ann NY Acad Sci 2013;1284(1):1–5. DOI: 10.1111/nyas.12105

13. Gerashchenko T., Frolova A., Patysheva M. et al. Breast Cancer immune landscape: interplay between systemic and local immunity. Adv Biol (Weinh) 2024;8(7):e2400140. DOI: 10.1002/adbi.202400140

14. Galluzzi L., Senovilla L., Zitvogel L. et al. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov 2012;11(3):215–33. DOI: 10.1038/nrd3626

15. Wang L., Geng H., Liu Y. et al. Hot and cold tumors: immunological features and the therapeutic strategies. MedComm (2020) 2023;4(5):e343. DOI: 10.1002/mco2.343

16. Opzoomer J.W., Sosnowska D., Anstee J.E. et al. Cytotoxic Chemotherapy as an immune stimulus: a molecular perspective on turning up the immunological heat on cancer. Front Immunol 2019;10:1654. DOI: 10.3389/fimmu.2019.01654

17. Merlano M.C., Denaro N., Galizia D. et al. How chemotherapy affects the tumor immune microenvironment: a narrative review. Biomedicines 2022;10(8):1822. DOI: 10.3390/biomedicines10081822

18. Zhang J., Pan S., Jian C. et al. Immunostimulatory properties of chemotherapy in breast cancer: from immunogenic modulation mechanisms to clinical practice. Front Immunol 2021;12:819405. DOI: 10.3389/fimmu.2021.819405

19. Kroemer G., Galassi C., Zitvogel L. et al. Immunogenic cell stress and death. Nat Immunol 2022;23(4):487–500. DOI: 10.1038/s41590-022-01132-2

20. Kroemer G., Galluzzi L., Kepp O. et al. Immunogenic cell death in cancer therapy. Annu Rev Immunol 2013;31:51–72. DOI: 10.1146/annurev-immunol-032712-100008

21. Zitvogel L., Apetoh L., Ghiringhelli F. et al. The anticancer immune response: indispensable for therapeutic success? J Clin Invest 2008;118(6):1991–2001. DOI: 10.1172/jci35180

22. Russo M., Panini N., Fabbrizio P. et al. Chemotherapy-induced neutropenia elicits metastasis formation in mice by promoting proliferation of disseminated tumor cells. Oncoimmunology 2023;12(1):2239035. DOI: 10.1080/2162402x.2023.2239035

23. Sistigu A., Yamazaki T., Vacchelli E. et al. Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat Med 2014;20(11):1301–9. DOI: 10.1038/nm.3708

24. Benson Z., Manjili S.H., Habibi M. et al. Conditioning neoadjuvant therapies for improved immunotherapy of cancer. Biochem Pharmacol 2017;145:12–7. DOI: 10.1016/j.bcp.2017.08.007

25. Patysheva M., Larionova I., Stakheyeva M. et al. Effect of earlystage human breast carcinoma on monocyte programming. Front Oncol 2021;11:800235. DOI: 10.3389/fonc.2021.800235

26. Романов Б.К., Дмитриева Н.Б., Зацепилова Т.А. Противоопухолевые препараты. Medical Journal of the Russian Federation, Russian Journal 2018;24(3):146–50. DOI: 10.18821/0869-2106-2018-24-3-146-150

27. Wu J., Waxman D.J. Immunogenic chemotherapy: dose and schedule dependence and combination with immunotherapy. Cancer Lett 2018;419:210–21. DOI: 10.1016/j.canlet.2018.01.050

28. Трякин А.А., Бесова Н.С., Волков Н.М. и др. Общие принципы противоопухолевой лекарственной терапии. Злокачественные опухоли 2024;14(3s2–1):33–46. DOI: 10.18027/2224-5057-2024-14-3s2-1.1-01

29. Трякин А.А., Бесова Н.С., Волков Н.М. и др. Практические рекомендации по общим принципам проведения противоопухолевой лекарственной терапии. Злокачественные опухоли 2020;10(3s2–1):26–39. DOI: 10.18027/2224-5057-2020-10-3s2-01

30. Лактионов К.К., Артамонова Е.В., Бредер В.В. и др. Немелкоклеточный рак легкого. Злокачественные опухоли 2024;14(3s2–1): 65–104. DOI: 10.18027/2224-5057-2024-14-3s2-1.1-04

31. Чубенко В.А., Бычков М.Б., Деньгина Н.В. и др. Мелкоклеточный рак легкого. Злокачественные опухоли 2024;14(3s2–1): 105–114. DOI: 10.18027/2224-5057-2024-14-3s2-1.1-05

32. Строяковский Д.Л., Абрамов М.Е., Демидов Л.В. и др. Меланома кожи. Злокачественные опухоли 2024;14(3s2):300–29. DOI: 10.18027/2224-5057-2024-14-3s2-1.2-12

33. Тюляндин С.А., Артамонова Е.В., Жигулев А.Н. и др. Рак молочной железы. Злокачественные опухоли 2024;14(3s2–2):32–81. DOI: 10.18027/2224-5057-2024-14-3s2-1.2-01

34. Хохлова С.В., Кравец О.А., Морхов К.Ю. и др. Рак шейки матки. Злокачественные опухоли 2024;14(3s2–2):136–64. DOI: 10.18027/2224-5057-2024-14-3s2-1.2-05

35. Покатаев И.А., Дудина И.А., Коломиец Л.А. и др. Рак яичников, первичный рак брюшины и рак маточных труб. Злокачественные опухоли 2024;14(3s2–2):82–101. DOI: 10.18027/2224-5057-2024-14-3s2-1.2-02

36. Болотина Л.В., Владимирова Л.Ю., Деньгина Н.В. и др. Опухоли головы и шеи. Злокачественные опухоли 2024; 14(3s2–1):160–82. DOI: 10.18027/2224-5057-2024-14-3s2-1.1-09

37. Улитин А.Ю., Желудкова О.Г., Иванов П.И. и др. Первичные опухоли центральной нервной системы. Злокачественные опухоли 2024;14(3s2–1):183–211. DOI: 10.18027/2224-5057-2024-14-3s2-1.1-10

38. Трякин А.А., Бесова Н.С., Волков Н.М. и др. Рак пищевода и пищеводно-желудочного перехода. Злокачественные опухоли 2024;14(3s2-1):221–240. DOI: 10.18027/2224-5057-2024-14-3s2-1.1-12

39. Бесова Н.С., Болотина Л.В., Гамаюнов С.В. и др. Рак желудка. Злокачественные опухоли 2024;14(3s2–1):241–62. DOI: 10.18027/2224-5057-2024-14-3s2-1.1-13

40. Кудашкин Н.Е., Гладков О.А., Загайнов В.Е. и др. Рак поджелудочной железы. Злокачественные опухоли 2024;14(3s2–1): 404–15. DOI: 10.18027/2224-5057-2024-14-3s2-1.1-18

41. Федянин М.Ю., Гладков О.А., Гордеев С.С. и др. Рак ободочной кишки, ректосигмоидного соединения и прямой кишки. Злокачественные опухоли 2024;14(3s2–1):263–322. DOI: 10.18027/2224-5057-2024-14-3s2-1.1-14

42. Матвеев В.Б., Волкова М.И., Гладков О.А. и др. Герминогенные опухоли у мужчин. Злокачественные опухоли 2024;14(3s2–2): 267–99. DOI: 10.18027/2224-5057-2024-14-3s2-1.2-11

43. Румянцев А.А., Булычкин П.В., Волкова М.И. и др. Рак мочевого пузыря. Злокачественные опухоли 2024;14(3s2–2):221–41. DOI: 10.18027/2224-5057-2024-14-3s2-1.2-09

44. Егоренков В.В., Бохян А.Ю., Конев А.А. и др. Саркомы мягких тканей. Злокачественные опухоли 2024;14(3s2–2):393–413. DOI: 10.18027/2224-5057-2024-14-3s2-1.2-15

45. Bukowski K., Kciuk M., Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci 2020;21(9):3233. DOI: 10.3390/ijms21093233

46. Olofinsan K., Abrahamse H., George B.P. Therapeutic role of alkaloids and alkaloid derivatives in cancer management. Molecules 2023;28(14):5578. DOI: 10.3390/molecules28145578

47. Ostios-Garcia L., Pérez D.M., Castelo B. et al. Classification of anticancer drugs: an update with FDA- and EMA-approved drugs. Cancer Metastasis Rev 2024;43(4):1561–71. DOI: 10.1007/s10555-024-10188-5

48. Gebremeskel S., Johnston B. Concepts and mechanisms underlying chemotherapy induced immunogenic cell death: impact on clinical studies and considerations for combined therapies. Oncotarget 2015;6(39):41600–19. DOI: 10.18632/oncotarget.6113

49. Gerashchenko T.S., Patysheva M.R., Fedorenko A.A. et al. Chemotherapy-induced developmental trajectories of monocytes in breast cancer. RUDN Journal of MEDICIN 2024;28(4):427–38. DOI: 10.22363/2313-0245-2024-28-4-427-438

50. Karati D., Mahadik K.R., Trivedi P. et al. Alkylating agents, the road less traversed, changing anticancer therapy. Anticancer Agents Med Chem 2022;22(8):1478–95. DOI: 10.2174/1871520621666210811105344

51. Khoury A., Deo K.M., Aldrich-Wright J.R. Recent advances in platinum-based chemotherapeutics that exhibit inhibitory and targeted mechanisms of action. J Inorg Biochem 2020;207:111070. DOI: 10.1016/j.jinorgbio.2020.111070

52. Bayat Mokhtari R., Homayouni T.S., Baluch N. et al. Combination therapy in combating cancer. Oncotarget 2017;8(23):38022–43. DOI: 10.18632/oncotarget.16723

53. Никитина О.Г., Валиахметова А.Р., Газдалиева Л.М. Применение химиотерапии при лечении онкологических больных. Международный студенческий научный вестник 2018;4(3):471–4.

54. Орлова О.Л., Николаева Л.Л., Король Л.А. и др. Современные онкопрепараты для внутреннего применения. Фармация и фармакология 2018;6(5):440–61. DOI: 10.19163/2307-9266-2018-6-5-440-461

55. Yoo J., Jung Y., Ahn J.H. et al. Incidence and clinical course of septic shock in neutropenic patients during chemotherapy for gynecological cancers. J Gynecol Oncol 2020;31(5):e62. DOI: 10.3802/jgo.2020.31.e62

56. Ahlmann M., Hempel G. The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy. Cancer Chemother Pharmacol 2016;78(4):661–71. DOI: 10.1007/s00280-016-3152-1

57. Kim C.G., Sohn J., Chon H. et al. Incidence of febrile neutropenia in korean female breast cancer patients receiving preoperative or postoperative doxorubicin/cyclophosphamide followed by docetaxel chemotherapy. J Breast Cancer 2016;19(1):76–82. DOI: 10.4048/jbc.2016.19.1.76

58. Lyman G.H., Michels S.L., Reynolds M.W. et al. Risk of mortality in patients with cancer who experience febrile neutropenia. Cancer 2010;116(23):5555–63. DOI: 10.1002/cncr.25332

59. Uitdehaag B.M., Nillesen W.M., Hommes O.R. Long-lasting effects of cyclophosphamide on lymphocytes in peripheral blood and spinal fluid. Acta Neurol Scand 1989;79(1):12–7. DOI: 10.1111/j.1600-0404.1989.tb03702.x

60. Emadi A., Jones R.J., Brodsky R.A. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol 2009;6(11):638–47. DOI: 10.1038/nrclinonc.2009.146

61. Ghiringhelli F., Menard C., Puig P.E. et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 2007;56(5):641–8. DOI: 10.1007/s00262-006-0225-8

62. Dimeloe S., Frick C., Fischer M. et al. Human regulatory T cells lack the cyclophosphamide-extruding transporter ABCB1 and are more susceptible to cyclophosphamide-induced apoptosis. Eur J Immunol 2014;44(12):3614–20. DOI: 10.1002/eji.201444879

63. Huijts C.M., Lougheed S.M., Bodalal Z. et al. The effect of everolimus and low-dose cyclophosphamide on immune cell subsets in patients with metastatic renal cell carcinoma: results from a phase I clinical trial. Cancer Immunol Immunother 2019;68(3):503–15. DOI: 10.1007/s00262-018-2288-8

64. Nakahara T., Uchi H., Lesokhin A.M. et al. Cyclophosphamide enhances immunity by modulating the balance of dendritic cell subsets in lymphoid organs. Blood 2010;115(22):4384–92. DOI: 10.1182/blood-2009-11-251231

65. Bao L., Hao C., Wang J. et al. High-dose cyclophosphamide administration orchestrates phenotypic and functional alterations of immature dendritic cells and regulates th cell polarization. Front Pharmacol 2020;11:775. DOI: 10.3389/fphar.2020.00775

66. Larionova I., Cherdyntseva N., Liu T. et al. Interaction of tumorassociated macrophages and cancer chemotherapy. Oncoimmunology 2019;8(7):1596004. DOI: 10.1080/2162402x.2019.1596004

67. Bart V.M.T., Pickering R.J., Taylor P.R. et al. Macrophage reprogramming for therapy. Immunology 2021;163(2):128–44. DOI: 10.1111/imm.13300

68. Heath O., Berlato C., Maniati E. et al. Chemotherapy induces tumor-associated macrophages that aid adaptive immune responses in ovarian cancer. Cancer Immunol Res 2021;9(6):665–81. DOI: 10.1158/2326-6066.Cir-20-0968

69. Sevko A., Sade-Feldman M., Kanterman J. et al. Cyclophosphamide promotes chronic inflammation-dependent immunosuppression and prevents antitumor response in melanoma. J Invest Dermatol 2013;133(6):1610–1619. DOI: 10.1038/jid.2012.444

70. Longley D.B., Harkin D.P., Johnston P.G. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003;3(5):330–8. DOI: 10.1038/nrc1074

71. Cavalcanti I.D.L., Soares J.C.S. Conventional cancer treatment. In: Advances in Cancer Treatment: From Systemic Chemotherapy to Targeted Therapy. Ed. by I.D.L. Cavalcanti, J.C.S. Soares. Cham: Springer International Publishing, 2021. Pp. 29–56.

72. Al-Shammary E.H., Mohammed D.J. Chemotherapy-induced neutropenia after initial and subsequent chemotherapy cycle of non-Hodgkin lymphoma. Mustansiriya Med J 2020;19(1):16–9. DOI: 10.4103/mj.Mj_4_20

73. Bracci L., Schiavoni G., Sistigu A. et al. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ 2014;21(1):15–25. DOI: 10.1038/cdd.2013.67

74. Nowak A.K., Robinson B.W., Lake R.A. Gemcitabine exerts a selective effect on the humoral immune response: implications for combination chemo-immunotherapy. Cancer Res 2002;62(8):2353–8

75. Herman S., Zurgil N., and Deutsch M. Low dose methotrexate induces apoptosis with reactive oxygen species involvement in T lymphocytic cell lines to a greater extent than in monocytic lines. Inflamm Res 2005;54(7):273–80. DOI: 10.1007/s00011-005-1355-8

76. Eriksson E., Wenthe J., Irenaeus S. et al. Gemcitabine reduces MDSCs, tregs and TGFβ-1 while restoring the teff/treg ratio in patients with pancreatic cancer. J Transl Med 2016;14(1):282. DOI: 10.1186/s12967-016-1037-z

77. Sawasdee N., Thepmalee C., Sujjitjoon J. et al. Gemcitabine enhances cytotoxic activity of effector T-lymphocytes against chemo-resistant cholangiocarcinoma cells. Int Immunopharmacol 2020;78:106006. DOI: 10.1016/j.intimp.2019.106006

78. Szczygieł A., Węgierek-Ciura K., Mierzejewska J. et al. The modulation of local and systemic anti-tumor immune response induced by methotrexate nanoconjugate in murine MC38 colon carcinoma and B16 F0 melanoma tumor models. Am J Cancer Res 2023;13(10):4623–43.

79. Ma G., Zhang Z., Li P. et al. Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment. Cell Commun Signal 2022;20(1):114. DOI: 10.1186/s12964-022-00909-0

80. Cerezo M., Rocchi S. Cancer cell metabolic reprogramming: a keystone for the response to immunotherapy. Cell Death Disease 2020;11(11):964. DOI: 10.1038/s41419-020-03175-5

81. Fang H., Ang B., Xu X. et al. TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells. Cell Mol Immunol 2014;11(2):150–9. DOI: 10.1038/cmi.2013.59

82. Apetoh L., Ladoire S., Coukos G. et al. Combining immunotherapy and anticancer agents: the right path to achieve cancer cure? Ann Oncol 2015;26(9):1813–23. DOI: 10.1093/annonc/mdv209

83. Püschel F., Favaro F., Redondo-Pedraza J. et al. Starvation and antimetabolic therapy promote cytokine release and recruitment of immune cells. Proc Natl Acad Sci USA 2020;117(18):9932–41. DOI: 10.1073/pnas.1913707117

84. Malesci A., Bianchi P., Celesti G. et al. Tumor-associated macrophages and response to 5-fluorouracil adjuvant therapy in stage III colorectal cancer. Oncoimmunology 2017;6(12):e1342918. DOI: 10.1080/2162402x.2017.1342918

85. Yokoyama C., Sueyoshi Y., Ema M. et al. Induction of oxidative stress by anticancer drugs in the presence and absence of cells. Oncol Lett 2017;14(5):6066–70. DOI: 10.3892/ol.2017.6931

86. Mordente A., Meucci E., Silvestrini A. et al. Anthracyclines and Mitochondria. In: Advances in mitochondrial medicine. Ed. by R. Scatena, P. Bottoni, B. Giardina. Dordrecht: Springer Netherlands, 2012. Pp. 385–419.

87. Steele T.A. Chemotherapy-induced immunosuppression and reconstitution of immune function. Leuk Res 2002;26(4):411–4. DOI: 10.1016/S0145-2126(01)00138-2

88. Krysko D.V., Kaczmarek A., Krysko O. et al. TLR-2 and TLR-9 are sensors of apoptosis in a mouse model of doxorubicin-induced acute inflammation. Cell Death Differ 2011;18(8):1316–25. DOI: 10.1038/cdd.2011.4

89. Ghiringhelli F., Apetoh L., Tesniere A. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors. Nat Med 2009;15(10):1170–8. DOI: 10.1038/nm.2028

90. Obeid M., Tesniere A., Ghiringhelli F. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 2007;13(1):54–61. DOI: 10.1038/nm1523

91. Giglio P., Mara G., Nicola T. et al. PKR and GCN2 stress kinases promote an ER stress-independent eIF2α phosphorylation responsible for calreticulin exposure in melanoma cells. OncoImmunology 2018;7(8):e1466765. DOI: 10.1080/2162402X.2018.1466765

92. Hodge J.W., Garnett C.T., Farsaci B. et al. Chemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death. Int J Cancer 2013;133(3):624–36. DOI: 10.1002/ijc.28070

93. Alizadeh D., Larmonier N. Chemotherapeutic targeting of cancerinduced immunosuppressive cells. Cancer Res 2014;74(10):2663–8. DOI: 10.1158/0008-5472.Can-14-0301

94. Park J.Y., Jang M.J., Chung Y.H. et al. Doxorubicin enhances CD4+ T-cell immune responses by inducing expression of CD40 ligand and 4-1BB. Int Immunopharmacol 2009;9(13):1530–9. DOI: 10.1016/j.intimp.2009.09.008

95. Mattarollo S.R., Loi S., Duret H. et al. Pivotal role of innate and adaptive immunity in anthracycline chemotherapy of established tumors. Cancer Res 2011;71(14):4809–20. DOI: 10.1158/0008-5472.Can-11-0753

96. Huang J., Wu R., Chen L. et al. Understanding anthracycline cardiotoxicity from mitochondrial aspect. Front Pharmacol 2022;13:811406. DOI: 10.3389/fphar.2022.811406

97. Ocadlikova D., Lecciso M., Isidori A. et al. Chemotherapy-induced tumor cell death at the crossroads between immunogenicity and immunotolerance: focus on acute myeloid leukemia. Front Oncol 2019;9:1004. DOI: 10.3389/fonc.2019.01004

98. Wijayahadi N., Haron M.R., Stanslas J. et al. Changes in cellular immunity during chemotherapy for primary breast cancer with anthracycline regimens. J Chemother 2007;19(6):716–23. DOI: 10.1179/joc.2007.19.6.716

99. Elsea C.R., Roberts D.A., Druker B.J. et al. Inhibition of p38 MAPK suppresses inflammatory cytokine induction by etoposide, 5-fluorouracil, and doxorubicin without affecting tumoricidal activity. PLoS One 2008;3(6):e2355. DOI: 10.1371/journal.pone.0002355

100. Sauter K.A., Wood L.J., Wong J. et al. Doxorubicin and daunorubicin induce processing and release of interleukin-1β through activation of the NLRP3 inflammasome. Cancer Biol Ther 2011;11(12):1008–16. DOI: 10.4161/cbt.11.12.15540

101. Wang L., Chen Q., Qi H. et al. Doxorubicin-induced systemic inflammation is driven by upregulation of toll-like receptor TLR4 and endotoxin leakage. Cancer Res 2016;76(22):6631–42. DOI: 10.1158/0008-5472.Can-15-3034

102. Singh A., Kaur N., Singh G. et al. Topoisomerase I and II inhibitors: a patent review. Recent Pat Anticancer Drug Discov 2016;11(4):401–23. DOI: 10.2174/0929866523666160720095940

103. Yakkala P.A., Penumallu N.R., Shafi S. et al. Prospects of topoisomerase inhibitors as promising anti-cancer agents. Pharmaceuticals (Basel) 2023;16(10):1456. DOI: 10.3390/ph16101456

104. Kim G.M., Kim Y.S., Ae Kang Y. et al. Efficacy and toxicity of belotecan for relapsed or refractory small cell lung cancer patients. J Thorac Oncol 2012;7(4):731–6. DOI: 10.1097/JTO.0b013e31824b23cb

105. Dang X., Ogbu S.C., Zhao J. et al. Inhibition of topoisomerase IIA (Top2α) induces telomeric DNA damage and T cell dysfunction during chronic viral infection. Cell Death Dis 2020;11(3):196. DOI: 10.1038/s41419-020-2395-2

106. Rialdi A., Campisi L., Zhao N. et al. Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation. Science 2016;352(6289):aad7993. DOI: 10.1126/science.aad7993

107. Haggerty T.J., Dunn I.S., Rose L.B. et al. Topoisomerase inhibitors modulate expression of melanocytic antigens and enhance T cell recognition of tumor cells. Cancer Immunol Immunother 2011;60(1):133–44. DOI: 10.1007/s00262-010-0926-x

108. Wan S., Pestka S., Jubin R.G. et al. Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells. PLoS One 2012;7(3):e32542. DOI: 10.1371/journal.pone.0032542

109. Mckenzie J.A., Mbofung R.M., Malu S. et al. The effect of topoisomerase i inhibitors on the efficacy of T-cell-based cancer immunotherapy. J Natl Cancer Inst 2018;110(7):777–86. DOI: 10.1093/jnci/djx257

110. Lee J.-M., Shin K.-S., Koh C.-H. et al. Inhibition of topoisomerase I shapes antitumor immunity through the induction of monocyte-derived dendritic cells. Cancer Lett 2021;520:38–47. DOI: 10.1016/j.canlet.2021.06.031

111. Iwai T., Sugimoto M., Wakita D. et al. Topoisomerase I inhibitor, irinotecan, depletes regulatory T cells and up-regulates MHC class I and PD-L1 expression, resulting in a supra-additive antitumor effect when combined with anti-PD-L1 antibodies. Oncotarget 2018;9(59):31411–21. DOI: 10.18632/oncotarget.25830

112. Matsuura H.N., Fett-Neto A.G. Plant alkaloids: main features, toxicity, and mechanisms of action. In: Plant toxins. Ed. by P. Gopalakrishnakone, C.R. Carlini, R. Ligabue-Braun. Dordrecht: Springer Netherlands, 2015. Pp. 1–15.

113. Khan H., Alam W., Alsharif K.F. et al. Alkaloids and colon cancer: molecular mechanisms and therapeutic implications for cell cycle arrest. Molecules 2022;27(3):920. DOI: 10.3390/molecules27030920

114. Taub J.W., Buck S.A., Xavier A.C. et al. The evolution and history of vinca alkaloids: from the big bang to the treatment of pediatric acute leukemia. Pediatr Blood Cancer 2024;71(11):e31247. DOI: 10.1002/pbc.31247

115. Markman J., Zanotti K., Webster K. et al. Experience with the management of neutropenia in gynecologic cancer patients receiving carboplatin-based chemotherapy. Gynecol Oncol 2004;92(2):592–5. DOI: 10.1016/j.ygyno.2003.11.005

116. Markman M. Management of toxicities associated with the administration of taxanes. Exp Opin Drug Saf 2003;2(2):141–6. DOI: 10.1517/14740338.2.2.141

117. Beretta G.L., Cassinelli G., Rossi G. et al. Novel insights into taxane pharmacology: An update on drug resistance mechanisms, immunomodulation and drug delivery strategies. Drug Resist Updates 2025;81:101223. DOI: 10.1016/j.drup.2025.101223

118. Serpico A.F., Pisauro C., Grieco D. cGAS-dependent proinflammatory and immune homeostatic effects of the microtubule-targeting agent paclitaxel. Front Immunol 2023;14:1127623. DOI: 10.3389/fimmu.2023.1127623

119. Kaneno R., Shurin G.V., Tourkova I.L. et al. Chemomodulation of human dendritic cell function by antineoplastic agents in low noncytotoxic concentrations. J Translat Med 2009;7(1):58. DOI: 10.1186/1479-5876-7-58

120. Pfannenstiel L.W., Lam S.S., Emens L.A. et al. Paclitaxel enhances early dendritic cell maturation and function through TLR4 signaling in mice. Cell Immunol 2010;263(1):79–87. DOI: 10.1016/j.cellimm.2010.03.001

121. Ramakrishnan R., Assudani D., Nagaraj S. et al. Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. J Clin Invest 2010;120(4):1111–24. DOI: 10.1172/jci40269

122. Pellicciotta I., Yang C.P., Goldberg G.L. et al. Epothilone B enhances class I HLA and HLA-A2 surface molecule expression in ovarian cancer cells. Gynecol Oncol 2011;122(3):625–31. DOI: 10.1016/j.ygyno.2011.05.007

123. Wanderley C.W., Colón D.F., Luiz J.P.M. et al. Paclitaxel reduces tumor growth by reprogramming tumor-associated macrophages to an M1 profile in a TLR4-dependent manner. Cancer Res 2018;78(20):5891–900. DOI: 10.1158/0008-5472.Can-17-3480

124. Dos Santos Guimarães I., Ladislau-Magescky T., Tessarollo N.G. et al. Chemosensitizing effects of metformin on cisplatin- and paclitaxelresistant ovarian cancer cell lines. Pharmacol Rep 2018;70(3):409–17. DOI: 10.1016/j.pharep.2017.11.007

125. Pusztai L., Mendoza T.R., Reuben J.M. et al. Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy. Cytokine 2004;25(3):94–102. DOI: 10.1016/j.cyto.2003.10.004

126. Laha D., Grant R., Mishra P. et al. The role of tumor necrosis factor in manipulating the immunological response of tumor microenvironment. Front Immunol 2021;12:656908. DOI: 10.3389/fimmu.2021.656908

127. Tsavaris N., Kosmas C., Vadiaka M. et al. Immune changes in patients with advanced breast cancer undergoing chemotherapy with taxanes. Br J Cancer 2002;87(1):21–7. DOI: 10.1038/sj.bjc.6600347

128. Sun Y., Ma X., Hu H. Application of nano-drug delivery system based on cascade technology in cancer treatment. Int J Mol Sci 2021;22(11):5698. DOI: 10.3390/ijms22115698

129. D’incalci M., Badri N., Galmarini C.M. et al. Trabectedin, a drug acting on both cancer cells and the tumour microenvironment. Br J Cancer 2014;111(4):646–50. DOI: 10.1038/bjc.2014.149

130. Germano G., Frapolli R., Belgiovine C. et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 2013;23(2):249–62. DOI: 10.1016/j.ccr.2013.01.008

131. Blackburn G.L. Metabolic considerations in management of surgical patients. Surg Clin North Am 2011;91(3):467–80. DOI: 10.1016/j.suc.2011.03.001

132. Кадагидзе З.Г., Черткова А.И. Иммунная система и рак. Практическая онкология 2016;17(2):62–73. DOI: 10.31917/1702062

133. Hiam-Galvez K.J., Allen B.M., Spitzer M.H. Systemic immunity in cancer. Nat Rev Cancer 2021;21(6):345–59. DOI: 10.1038/s41568-021-00347-z

134. Zou W., Wolchok J.D., Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med 2016;8(328):328rv324. DOI: 10.1126/scitranslmed.aad7118

135. Tilsed C.M., Fisher S.A., Nowak A.K. et al. Cancer chemotherapy: insights into cellular and tumor microenvironmental mechanisms of action. Front Oncol 2022;12:960317. DOI: 10.3389/fonc.2022.960317

136. Новик А.В., Проценко С.А., Балдуева И.А. Использование оценки состояния адаптивной иммунной системы у больных со злокачественными солидными опухолями в качестве предиктивных или прогностических факторов: систематический обзор. Эффективная фармакотерапия 2020;16(33):58–75. DOI: 10.33978/2307-3586-2020-16-33-58-75

137. Артамонова Е.В. Место иммуномодуляторов в терапии рака молочной железы. Опухоли женской репродуктивной системы 2007;1(2):23–6.

138. Сагакянц А.Б., Белякова Л.И., Шевченко А.Н. и др. Особенности локального иммунитета у пациентов с неинвазивномышечным раком мочевого пузыря различной степени злокачественности. Южно-Российский онкологический журнал 2022;3(4):58–66. DOI: 10.37748/2686-9039-2022-3-4-6

139. Стахеева М.Н., Эйдензон Д., Слонимская Е.М. и др. Взаимосвязь состояния иммунной системы как интегрированного целого с клиническим течением рака молочной железы. Сибирский онкологический журнал 2011;2(44):11–9.

140. Stakheyeva M., Eidenzon D., Slonimskaya E. et al. Integral characteristic of the immune system state predicts breast cancer outcome. Exp Oncol 2019;41(1):32–8.

141. Adhikary S., Pathak S., Palani V. et al. Current technologies and future perspectives in immunotherapy towards a clinical oncology approach. Biomedicines 2024;12(1):217. DOI: 10.3390/biomedicines12010217

142. Рыбкина В.Л., Адамова Г.В., Ослина Д.С. Роль цитокинов в патогенезе злокачественных новообразований. Сибирский научный медицинский журнал 2023;43(2):15–28. DOI: 10.18699/SSMJ20230202

143. Fu Y., Tang R., Zhao X. Engineering cytokines for cancer immunotherapy: a systematic review. Front Immunol 2023;14:1218082. DOI: 10.3389/fimmu.2023.1218082

144. Владимирова Л.Ю., Непомнящая Е.М., Подзорова Н.А. и др. Рекомбинантный фактор некроза опухоли-тимозин-α1: влияние на эффективность неоадъювантной химиотерапии и неоангиогенез при раке молочной железы. Вопросы онкологии 2017;63(1):76–81. DOI: 10.37469/0507-3758-2017-63-1-76-81

145. Илюшин А.Л., Богдашин И.В., Алексанян А.З. и др. Интерферон-γ и опухолевый рост. Сибирский онкологический журнал 2023;22(4):118–27. DOI: 10.21294/1814-4861-2023-22-4-118-127

146. Исаева В.Г., Гривцова Л.Ю., Жовтун Л.П. и др. Противоопухолевый эффект рекомбинантного интерферона гамма в экспериментальной модели билатеральной солидной карциномы Эрлиха. Успехи молекулярной онкологии 2022;9(2):111–9. DOI: 10.17650/2313-805X-2022-9-2-111-119

147. Стахеева М.Н., Богдашин И.В., Тарабановская Н.А. и др. Клинический случай ингаляционного применения цитокинов у больной раком молочной железы с образованиями в легком неясного генеза. Иммунология 2024;45(3):321–8.

148. Galluzzi L., Vitale I., Warren S. et al. Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. J Immunother Cancer 2020;8(1):e000337. DOI: 10.1136/jitc-2019-000337

149. Galluzzi L., Buqué A., Kepp O. et al. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 2015;28(6):690–714. DOI: 10.1016/j.ccell.2015.10.012

150. Bailly C., Thuru X., Quesnel B. Combined cytotoxic chemotherapy and immunotherapy of cancer: modern times. NAR Cancer 2020;2(1):zcaa002. DOI: 10.1093/narcan/zcaa002