Multiple aspects of the chemotherapy effect on immune response
https://doi.org/10.17650/2313-805X-2025-12-3-8-25
Abstract
Suppression of tumor cell growth and proliferation is the main goal of chemotherapy which is an integral part of the treatment for cancer patients. In addition to high antitumor activity, the cytotoxic effects of chemotherapeutic agents also extend to immune cells, resulting in pancytopenia and weakened immune response. Nevertheless, the effect of chemotherapy on the immune system is multifaceted, as it simultaneously exerts a suppressive influence while also stimulating the antitumor activity of lymphoid and myeloid populations. This review focuses on the analysis and generalization of modern data regarding the effects of chemotherapeutic drugs used in standard antitumor therapy regimens on the functioning of the immune system. The suppressive mechanisms of chemotherapy, including the development of cytopenia, are reviewed. Special attention is paid to the analysis of data on modulation of antitumor immune response depending on the class of chemotherapeutic agent. Mechanisms enhancing immune recognition and stimulating immune cells in response to increased expression of tumor antigens are described. The data regarding the effects of chemotherapy on the tumor microenvironment, including the reprogramming of immunosuppressive profiles and the activation of immune effectors, is presented. The summarized data underscore the dual nature of chemotherapy’s effects on the state of the immune system and its influence on the formation of antitumor immune responses.
About the Authors
A. A. FedorenkoRussian Federation
Anastasia Alekseevna Fedorenko
5 Kooperativny Line, Tomsk 634009, Russia; 36 Lenin Prospekt, Tomsk 634050, Russia
M. R. Patysheva
Russian Federation
5 Kooperativny Line, Tomsk 634009, Russia
A. A. Fedorov
Russian Federation
5 Kooperativny Line, Tomsk 634009, Russia
M. N. Stakheyeva
Russian Federation
5 Kooperativny Line, Tomsk 634009, Russia
N. V. Cherdyntseva
Russian Federation
5 Kooperativny Line, Tomsk 634009, Russia; 36 Lenin Prospekt, Tomsk 634050, Russia
T. S. Gerashchenko
Russian Federation
5 Kooperativny Line, Tomsk 634009, Russia
References
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. Romanov B.K., Dmitrieva N.B., Zatsepilova T.A. Antitumor drugs. Medical Journal of the Russian Federation, Russian Journal 2018;24(3):146–50. (In Russ.). 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. Tryakin A.A., Besova N.S., Volkov N.M. et al. General principles of antitumor drug therapy. Zlokachestvennye opukholi = Malignant Tumors 2024;14(3s2–1):33–46. (In Russ.). DOI: 10.18027/2224-5057-2024-14-3s2-1.1-01
29. Tryakin A.A., Besova N.S., Volkov N.M. et al. Practical recommendations on the general principles of antitumor drug therapy. Zlokachestvennye opukholi = Malignant Tumors 2020;10(3s2–1): 26–39. (In Russ.). DOI: 10.18027/2224-5057-2020-10-3s2-01
30. Laktionov K.K., Artamonova E.V., Breder V.V. et al. Non-small cell lung cancer. Zlokachestvennye opukholi = Malignant Tumors 2024;14(3s2–1):65–104. (In Russ.). DOI: 10.18027/2224-5057-2024-14-3s2-1.1-04
31. Chubenko V.A., Bychkov M.B., Dengina N.V. et al. Small cell lung cancer. Zlokachestvennye opukholi = Malignant Tumors 2024;14(3s2–1):105–14. (In Russ.). DOI: 10.18027/2224-5057-2024-14-3s2-1.1-05
32. Stroyakovsky D.L., Abramov M.E., Demidov L.V. et al. Melanoma of the skin. Zlokachestvennye opukholi = Malignant Tumors 2024;14(3s2):300–29. (In Russ.). DOI: 10.18027/2224-5057-2024-14-3s2-1.2-12
33. Tyulandin S.A., Artamonova E.V., Zhigulev A.N. et al. Breast cancer. Zlokachestvennye opukholi = Malignant Tumors 2024;14(3s2–2):32–81. (In Russ.). DOI: 10.18027/2224-5057-2024-14-3s2-1.2-01
34. Khokhlova S.V., Kravets O.A., Morkhov K.Yu. et al. Cervical cancer. Zlokachestvennye opukholi = Malignant Tumors 2024;14(3s2–2): 136–64. (In Russ.). DOI: 10.18027/2224-5057-2024-14-3s2-1.2-05
35. Pokataev I.A., Dudina I.A., Kolomiets L.A. et al. Ovarian cancer, primary peritoneal cancer, and fallopian tube cancer. Zlokachestvennye opukholi = Malignant Tumors 2024;14(3s2–2): 82–101. (In Russ.). DOI: 10.18027/2224-5057-2024-14-3s2-1.2-02
36. Bolotina L.V., Vladimirova L.Yu., Dengina N.V. et al. Tumors of the head and neck. Zlokachestvennye opukholi = Malignant Tumors 2024;14(3s2–1):160–82. (In Russ.). DOI: 10.18027/2224-5057-2024-14-3s2-1.1-09
37. Ulitin A.Yu., Zheludkova O.G., Ivanov P.I. et al. Primary tumors of the central nervous system. Zlokachestvennye opukholi = Malignant Tumors 2024;14(3s2–1):183–211. (In Russ.). DOI: 10.18027/2224-5057-2024-14-3s2-1.1-10
38. Tryakin A.A., Besova N.S., Volkov N.M. et al. Cancer of the esophagus and esophageal-gastric junction. Zlokachestvennye opukholi = Malignant Tumors 2024;14(3s2–1):221–40. (In Russ.). DOI: 10.18027/2224-5057-2024-14-3s2-1.1-12
39. Besova N.S., Bolotina L.V., Gamayunov S.V. et al. Stomach cancer. Zlokachestvennye opukholi = Malignant Tumors 2024;14(3s2–1): 241–62. (In Russ.). DOI: 10.18027/2224-5057-2024-14-3s2-1.1-13
40. Kudashkin N.E., Gladkov O.A., Zagainov V.E. et al. Pancreatic cancer. Zlokachestvennye opukholi = Malignant Tumors 2024;14(3s2–1):404–15. (In Russ.). DOI: 10.18027/2224-5057-2024-14-3s2-1.1-18
41. Fedyanin M.Yu., Gladkov O.A., Gordeev S.S. et al. Cancer of the colon, rectosigmoid junction and rectum. Zlokachestvennye opukholi = Malignant Tumors 2024;14(3s2–1):263–322. (In Russ.). DOI: 10.18027/2224-5057-2024-14-3s2-1.1-14
42. Matveev V.B., Volkova M.I., Gladkov O.A. et al. Germinogenic tumors in men. Zlokachestvennye opukholi = Malignant Tumors 2024;14(3s2–2):267–99. (In Russ.). DOI: 10.18027/2224-5057-2024-14-3s2-1.2-11
43. Rumyantsev A.A., Bulychkin P.V., Volkova M.I. et al. Bladder cancer. Zlokachestvennye opukholi = Malignant Tumors 2024; 14(3s2–2):221–41. (In Russ.). DOI: 10.18027/2224-5057-2024-14-3s2-1.2-09
44. Egorenkov V.V., Bokhyan A.Yu., Konev A.A. et al. Soft tissue sarcomas. Zlokachestvennye opukholi = Malignant Tumors 2024;14(3s2–2):393–413. (In Russ.). 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. Nikitina O.G., Valiakhmetova A.R., Gazdalieva L.M. The use of chemotherapy in the treatment of cancer patients. Mezhdunarodny studencheskiy nauchny vestnik = International Student Scientific Bulletin 2018;4(3):471–4. (In Russ.).
54. Orlova O.L., Nikolaeva L.L., Korol L.A. et al. Modern cancer drugs for internal use. Farmatsiya i farmakologiya = Pharmacy and Pharmacology 2018;6(5):440–61. (In Russ.). 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. Kadagidze Z.G., Chertkova A.I. The immune system and cancer. Prakticheskaya onkologiya = Practical Oncology 2016;17(2):62–73. (In Russ.). 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. Novik A.V., Protsenko S.A., Baldueva I.A. The use of assessment of the state of the adaptive immune system in patients with malignant solid tumors as predictive or prognostic factors: a systematic review. Effektivnaya farmakoterapiya = Effective Pharmacotherapy 2020;16(33): 58–75. (In Russ.). DOI: 10.33978/2307-3586-2020-16-33-58-75
137. Artamonova E.V. The place of immunomodulators in breast cancer therapy. Opukholi zhenskoy reproduktivnoy sistemy = Tumors of the Female Reproductive System 2007;1(2):23–6. (In Russ.).
138. Sagakyants A.B., Belyakova L.I., Shevchenko A.N. et al. Features of local immunity in patients with noninvasive muscular bladder cancer of varying degrees of malignancy. Yuzhno-Rossiyskiy onkologicheskiy zhurnal = South Russian Journal of Oncology 2022;3(4):58–66. (In Russ.). DOI: 10.37748/2686-9039-2022-3-4-6
139. Staheeva M.N., Eidenzon D., Slonimskaya E.M. et al. The relationship of the state of the immune system as an integrated whole with the clinical course of breast cancer. Sibirskiy onkologicheskiy zhurnal = Siberian Journal of Oncology 2011;2(44):11–9. (In Russ.).
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. Rybkina V.L., Adamova G.V., Oslina D.S. The role of cytokines in the pathogenesis of malignant neoplasms. Sibirskiy onkologicheskiy zhurnal = Siberian Journal of Oncology 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. Vladimirova L.Yu., Nepomnyashchaya E.M., Podzorova N.A. et al. Recombinant tumor necrosis factor-thymosin-a1: effect on the effectiveness of neoadjuvant chemotherapy and neoangiogenesis in breast cancer. Voprosy onkologii = Oncology Issues 2017;63(1):76–81. (In Russ.). DOI: 10.37469/0507-3758-2017-63-1-76-81
145. Ilyushin A.L., Bogdashin I.V., Aleksanyan A.Z. et al. Interferon-γ and tumor growth. Sibirskiy onkologicheskiy zhurnal = Siberian Journal of Oncology 2023;22(4):118–27. (In Russ.). DOI: 10.21294/1814-4861-2023-22-4-118-127
146. Isaeva V.G., Grivtsova L.Y., Zhovtun L.P. et al. Antitumor effect of recombinant interferon-gamma in an experimental model of Ehrlich’s bilateral solid carcinoma. Uspekhi molekulyarnoy onkologii = Advances in Molecular Oncology 2022;9(2):111–9. (In Russ.). DOI: 10.17650/2313-805X-2022-9-2-111-119
147. Staheeva M.N., Bogdashin I.V., Tarabanovskaya N.A. et al. A clinical case of inhaled cytokines in a breast cancer patient with lung tumors of unknown origin. Immunologiya = Immunology 2024;45(3):321–8. (In Russ.).
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
Review
For citations:
Fedorenko A.A., Patysheva M.R., Fedorov A.A., Stakheyeva M.N., Cherdyntseva N.V., Gerashchenko T.S. Multiple aspects of the chemotherapy effect on immune response. Advances in Molecular Oncology. 2025;12(3):8-25. (In Russ.) https://doi.org/10.17650/2313-805X-2025-12-3-8-25