mesЭкстремальная биомедицинаExtreme Medicine3033-89643033-8972Centre for Strategic Planning of the Federal Medical and Biological Agency10.47183/mes.2025-299mes-299Research ArticleГЛАВНАЯ ТЕМА: АКТУАЛЬНЫЕ ВОПРОСЫ КЛИНИЧЕСКОЙ НЕВРОЛОГИИ И ИНСТРУМЕНТАЛЬНОЙ ДИАГНОСТИКИ ЗАБОЛЕВАНИЙ НЕРВНОЙ СИСТЕМЫMAIN TOPIC: TOPICAL ISSUES OF CLINICAL NEUROLOGY & NEUROLOGICAL DISORDER INSTRUMENTAL DIAGNOSTICSРоль регуляторных Т-лимфоцитов в формировании иммуносупрессивного микроокружения при глиобластомеRole of regulatory T lymphocytes in the formation of immunosuppressive microenvironment in glioblastomahttps://orcid.org/0009-0007-0032-3474ЯнышеваЭ. П.YanyshevaE. P.

Янышева Эльвира Петровна

Москва

Elvira P. Yanysheva

Moscow

ElviraY2000@yandex.ruhttps://orcid.org/0000-0003-1039-4245БаклаушевВ. П.BaklaushevV. P.

Баклаушев Владимир Павлович, д-р мед. наук

Москва

Vladimir P. Baklaushev, Dr. Sci. (Med.)

Moscow

baklaushev.vp@fnkc-fmba.ruhttps://orcid.org/0000-0003-3056-4889ЮсубалиеваГ. М.YusubalievaG. M.

Юсубалиева Гаухар Маратовна, канд. мед. наук

Москва

Gaukhar M. Yusubalieva, Cand. Sci. (Med.)

Moscow

kakonya@gmail.comФедеральный центр мозга и нейротехнологий Федерального медико-биологического агентства; Федеральный научно-клинический центр специализированных видов медицинской помощи и медицинских технологийРоссияFederal Center of Brain Research and Neurotechnologies; Federal Research and Clinical Center of Specialized Medical Care and Medical TechnologiesRussian FederationФедеральный центр мозга и нейротехнологий Федерального медико-биологического агентства; Федеральный научно-клинический центр специализированных видов медицинской помощи и медицинских технологий; Институт молекулярной биологии им. В.А. Энгельгардта Российской академии наук; Научно-исследовательский институт пульмонологии Федерального медико-биологического агентстваРоссияFederal Center of Brain Research and Neurotechnologies; Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies; Engelhardt Institute of Molecular Biology; Pulmonology Scientific Research InstituteRussian FederationФедеральный центр мозга и нейротехнологий Федерального медико-биологического агентства; Федеральный научно-клинический центр специализированных видов медицинской помощи и медицинских технологий; Институт молекулярной биологии им. В.А. Энгельгардта Российской академии наукРоссияFederal Center of Brain Research and Neurotechnologies; Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies; Engelhardt Institute of Molecular BiologyRussian Federation202526062025272183190Copyright © Янышева Э.П., Баклаушев В.П., Юсубалиева Г.М., 20252025Янышева Э.П., Баклаушев В.П., Юсубалиева Г.М.Yanysheva E.P., Baklaushev V.P., Yusubalieva G.M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.extrememedicine.ru/jour/article/view/299Введение

Введение. Глиобластома является серьезнейшей проблемой для современной нейроонкологии, поскольку представляет собой наиболее частую опухоль центральной нервной системы с крайне неблагоприятным прогнозом для пациентов. Применяемая в настоящий момент стандартная терапия недостаточно эффективна, поэтому существует необходимость в создании новых подходов.

Цель

Цель. Анализ механизмов функционирования регуляторных T-лимфоцитов (Treg) в микроокружении опухоли как потенциальной мишени для терапии, а также выявление перспективных терапевтических методов, используемых для снижения супрессорного действия регуляторных T-лимфоцитов при глиобластоме.

Обсуждение

Обсуждение. Устойчивость глиобластомы к противоопухолевому иммунитету и низкая эффективность некоторых видов лечения во многом обусловлена иммуносупрессивным микроокружением опухоли, одним из ключевых компонентов которого являются Treg. Они подавляют противоопухолевый ответ посредством секреции противовоспалительных цитокинов, перфоринов и гранзимов, а также экспрессии ингибиторных молекул. Препараты, селективно воздействующие на метаболические пути активации, дифференцировки и миграции регуляторных T-клеток, способны снижать их активность и общее число в микроокружении.

Выводы

Выводы. Treg могут выступать в качестве мишени для терапии, направленной на подавление иммуносупрессивного опухолевого микроокружения, снижение активности и прогрессирования глиобластомы. Новые подходы таргетной терапии могут внести изменения в существующие стандарты лечения глиобластомы.

Introduction

Introduction. Being the most common tumor of the central nervous system with an extremely unfavorable prognosis, glioblastoma remain to be a major health issue. Conventional neuro-oncological strategies demonstrate insufficient effectiveness, which requires the development of improved approaches.

Objective

Objective. Analysis of the mechanisms of functioning of regulatory T lymphocytes (Treg) in the tumor microenvironment as a potential target for therapy, as well as identification of promising therapeutic methods to reduce the suppressive effect of regulatory T lymphocytes in glioblastoma.

Discussion

Discussion. The resistance of glioblastoma against antitumor immunity and the low effectiveness of some types of treatment is largely related to the immunosuppressive microenvironment of the tumor, the key components of which are Treg. Tregs suppress the antitumor response through the secretion of anti-inflammatory cytokines, perforins, and granzymes, as well as the expression of inhibitory molecules. Drugs that selectively affect the metabolic pathways of activation, differentiation, and migration of regulatory T cells can reduce their activity and total number in the microenvironment.

Conclusions

Conclusions. Tregs can act as a target for therapy aimed at suppressing the immunosuppressive microenvironment of the tumor, reducing the activity and progression of glioblastoma. New targeted therapeutical approaches may supplement the existing standards of glioblastoma treatment.

регуляторные T-лимфоцитыглиобластомаглиомаопухолевое микроокружениеиммуносупрессияиммунотерапиясолидная опухольregulatory T lymphocytesglioblastomagliomatumor microenvironmentimmunosuppressionimmunotherapysolid tumorРабота выполнена в рамках государственного задания ФМБА России (НИР «Персонализированная платформа для постоперационной иммунотерапии глиобластом», шифр «TILs-Глиобластома») и гранта Российского научного фонда № 22-64-00057.the work was performed within the framework of the state assignment of the FMBA of Russia (research project “Personalized platform for postoperative glioblastoma immunotherapy”, cipher “TILs-Glioblastoma”) and grant from the Russian Science Foundation No. 22-64-00057.ReferencesMarenco-Hillembrand L, Wijesekera O, Suarez-Meade P, Mampre D, Jackson C, Peterson J, et al. Trends in glioblastoma: outcomes over time and type of intervention: a systematic evidence based analysis. J Neurooncol. 2020;147:297–307. https://doi.org/10.1007/s11060-020-03451-6Marenco-Hillembrand L, Wijesekera O, Suarez-Meade P, Mampre D, Jackson C, Peterson J, et al. Trends in glioblastoma: outcomes over time and type of intervention: a systematic evidence based analysis. J Neurooncol. 2020;147:297–307. https://doi.org/10.1007/s11060-020-03451-6Lah TT, Novak M, Breznik B. Brain malignancies: Glioblastoma and brain metastases. Seminars in Cancer Biology. 2020;60:262–73. https://doi.org/10.1016/j.semcancer.2019.10.010Lah TT, Novak M, Breznik B. Brain malignancies: Glioblastoma and brain metastases. Seminars in Cancer Biology. 2020;60:262–73. https://doi.org/10.1016/j.semcancer.2019.10.010Smith CJ, Perfetti TA, Chokshi C, Venugopal C, Ashford JW, Singh SK. Risk factors for glioblastoma are shared by other brain tumor types. Hum Exp Toxicol. 2024;43:9603271241241796. https://doi.org/10.1177/09603271241241796Smith CJ, Perfetti TA, Chokshi C, Venugopal C, Ashford JW, Singh SK. Risk factors for glioblastoma are shared by other brain tumor types. Hum Exp Toxicol. 2024;43:9603271241241796. https://doi.org/10.1177/09603271241241796Colopi A, Fuda S, Santi S, Onorato A, Cesarini V, Salvati M, et al. Impact of age and gender on glioblastoma onset, progression, and management. Mech Ageing Dev. 2023;211:111801. https://doi.org/10.1016/j.mad.2023.111801Colopi A, Fuda S, Santi S, Onorato A, Cesarini V, Salvati M, et al. Impact of age and gender on glioblastoma onset, progression, and management. Mech Ageing Dev. 2023;211:111801. https://doi.org/10.1016/j.mad.2023.111801Khan I, Mahfooz S, Elbasan EB, Karacam B, Oztanir MN, Hatiboglu MA. Targeting Glioblastoma: The Current State of Different Therapeutic Approaches. Curr Neuropharmacol. 2021;19:1701–15. https://doi.org/10.2174/1570159X19666210113152108Khan I, Mahfooz S, Elbasan EB, Karacam B, Oztanir MN, Hatiboglu MA. Targeting Glioblastoma: The Current State of Different Therapeutic Approaches. Curr Neuropharmacol. 2021;19:1701–15. https://doi.org/10.2174/1570159X19666210113152108Wu W, Klockow JL, Zhang M, Lafortune F, Chang E, Jin L, et al. Glioblastoma multiforme (GBM): An overview of current therapies and mechanisms of resistance. Pharmacological Research. 2021;171:105780. https://doi.org/10.1016/j.phrs.2021.105780Wu W, Klockow JL, Zhang M, Lafortune F, Chang E, Jin L, et al. Glioblastoma multiforme (GBM): An overview of current therapies and mechanisms of resistance. Pharmacological Research. 2021;171:105780. https://doi.org/10.1016/j.phrs.2021.105780Wang X, Ge Y, Hou Y, Wang X, Yan Z, Li Y, et al. Single-cell atlas reveals the immunosuppressive microenvironment and Treg cells landscapes in recurrent Glioblastoma. Cancer Gene Ther. 2024;31:790–801. https://doi.org/10.1038/s41417-024-00740-4Wang X, Ge Y, Hou Y, Wang X, Yan Z, Li Y, et al. Single-cell atlas reveals the immunosuppressive microenvironment and Treg cells landscapes in recurrent Glioblastoma. Cancer Gene Ther. 2024;31:790–801. https://doi.org/10.1038/s41417-024-00740-4Lin H, Liu C, Hu A, Zhang D, Yang H, Mao Y. Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives. J Hematol Oncol. 2024;17:31. https://doi.org/10.1186/s13045-024-01544-7Lin H, Liu C, Hu A, Zhang D, Yang H, Mao Y. Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives. J Hematol Oncol. 2024;17:31. https://doi.org/10.1186/s13045-024-01544-7Medikonda R, Dunn G, Rahman M, Fecci P, Lim M. A review of glioblastoma immunotherapy. J Neurooncol. 2021;151:41–53. https://doi.org/10.1007/s11060-020-03448-1Medikonda R, Dunn G, Rahman M, Fecci P, Lim M. A review of glioblastoma immunotherapy. J Neurooncol. 2021;151:41–53. https://doi.org/10.1007/s11060-020-03448-1Bikfalvi A, da Costa CA, Avril T, Barnier J-V, Bauchet L, Brisson L, et al. Challenges in glioblastoma research: focus on the tumor microenvironment. Trends Cancer. 2023;9:9–27. https://doi.org/10.1016/j.trecan.2022.09.005Bikfalvi A, da Costa CA, Avril T, Barnier J-V, Bauchet L, Brisson L, et al. Challenges in glioblastoma research: focus on the tumor microenvironment. Trends Cancer. 2023;9:9–27. https://doi.org/10.1016/j.trecan.2022.09.005Bugakova AS, Chudakova DA, Myzina MS, Yanysheva EP, Ozerskaya IV, Soboleva AV, et al. Non-Tumor Cells within the Tumor Microenvironment — The «Eminence Grise» of the Glioblastoma Pathogenesis and Potential Targets for Therapy. Cells. 2024;13. https://doi.org/10.3390/cells13100808Bugakova AS, Chudakova DA, Myzina MS, Yanysheva EP, Ozerskaya IV, Soboleva AV, et al. Non-Tumor Cells within the Tumor Microenvironment — The «Eminence Grise» of the Glioblastoma Pathogenesis and Potential Targets for Therapy. Cells. 2024;13. https://doi.org/10.3390/cells13100808Dinevska M, Widodo SS, Furst L, Cuzcano L, Fang Y, Mangiola S, et al. Cell signaling activation and extracellular matrix remodeling underpin glioma tumor microenvironment heterogeneity and organization. Cell Oncol (Dordr). 2023;46:589–602. https://doi.org/10.1007/s13402-022-00763-9Dinevska M, Widodo SS, Furst L, Cuzcano L, Fang Y, Mangiola S, et al. Cell signaling activation and extracellular matrix remodeling underpin glioma tumor microenvironment heterogeneity and organization. Cell Oncol (Dordr). 2023;46:589–602. https://doi.org/10.1007/s13402-022-00763-9Qiu R, Zhong Y, Li Q, Li Y, Fan H. Metabolic Remodeling in Glioma Immune Microenvironment: Intercellular Interactions Distinct From Peripheral Tumors. Front Cell Dev Biol. 2021;9:693215. https://doi.org/10.3389/fcell.2021.693215Qiu R, Zhong Y, Li Q, Li Y, Fan H. Metabolic Remodeling in Glioma Immune Microenvironment: Intercellular Interactions Distinct From Peripheral Tumors. Front Cell Dev Biol. 2021;9:693215. https://doi.org/10.3389/fcell.2021.693215Pereira MB, Barros LRC, Bracco PA, Vigo A, Boroni M, Bonamino MH, et al. Transcriptional characterization of immunological infiltrates and their relation with glioblastoma patients overall survival. Oncoimmunology. 2018;7:1431083. https://doi.org/10.1080/2162402X.2018.1431083Pereira MB, Barros LRC, Bracco PA, Vigo A, Boroni M, Bonamino MH, et al. Transcriptional characterization of immunological infiltrates and their relation with glioblastoma patients overall survival. Oncoimmunology. 2018;7:1431083. https://doi.org/10.1080/2162402X.2018.1431083Stepanenko AA, Sosnovtseva AO, Valikhov MP, Chernysheva AA, Abramova OV, Pavlov KA, et al. Systemic and local immunosuppression in glioblastoma and its prognostic significance. Front Immunol. 2024;15. https://doi.org/10.3389/fimmu.2024.1326753Stepanenko AA, Sosnovtseva AO, Valikhov MP, Chernysheva AA, Abramova OV, Pavlov KA, et al. Systemic and local immunosuppression in glioblastoma and its prognostic significance. Front Immunol. 2024;15. https://doi.org/10.3389/fimmu.2024.1326753Dapash M, Hou D, Castro B, Lee-Chang C, Lesniak MS. The Interplay between Glioblastoma and Its Microenvironment. Cells. 2021;10:2257. https://doi.org/10.3390/cells10092257Dapash M, Hou D, Castro B, Lee-Chang C, Lesniak MS. The Interplay between Glioblastoma and Its Microenvironment. Cells. 2021;10:2257. https://doi.org/10.3390/cells10092257Himes BT, Geiger PA, Ayasoufi K, Bhargav AG, Brown DA, Parney IF. Immunosuppression in Glioblastoma: Current Understanding and Therapeutic Implications. Front Oncol. 2021;11:770561. https://doi.org/10.3389/fonc.2021.770561Himes BT, Geiger PA, Ayasoufi K, Bhargav AG, Brown DA, Parney IF. Immunosuppression in Glioblastoma: Current Understanding and Therapeutic Implications. Front Oncol. 2021;11:770561. https://doi.org/10.3389/fonc.2021.770561Du M, Sun L, Guo J, Lv H. Macrophages and tumor-associated macrophages in the senescent microenvironment: From immunosuppressive TME to targeted tumor therapy. Pharmacological Research. 2024;204:107198. https://doi.org/10.1016/j.phrs.2024.107198Du M, Sun L, Guo J, Lv H. Macrophages and tumor-associated macrophages in the senescent microenvironment: From immunosuppressive TME to targeted tumor therapy. Pharmacological Research. 2024;204:107198. https://doi.org/10.1016/j.phrs.2024.107198Mi Y, Guo N, Luan J, Cheng J, Hu Z, Jiang P, et al. The Emerging Role of Myeloid-Derived Suppressor Cells in the Glioma Immune Suppressive Microenvironment. Front Immunol. 2020;11. https://doi.org/10.3389/fimmu.2020.00737Mi Y, Guo N, Luan J, Cheng J, Hu Z, Jiang P, et al. The Emerging Role of Myeloid-Derived Suppressor Cells in the Glioma Immune Suppressive Microenvironment. Front Immunol. 2020;11. https://doi.org/10.3389/fimmu.2020.00737Vilbois S, Xu Y, Ho P-C. Metabolic interplay: tumor macrophages and regulatory T cells. Trends Cancer. 2024;10:242–55. https://doi.org/10.1016/j.trecan.2023.11.007Vilbois S, Xu Y, Ho P-C. Metabolic interplay: tumor macrophages and regulatory T cells. Trends Cancer. 2024;10:242–55. https://doi.org/10.1016/j.trecan.2023.11.007Dysthe M, Parihar R. Myeloid-Derived Suppressor Cells in the Tumor Microenvironment. Adv Exp Med Biol. 2020;1224:117–40. https://doi.org/10.1007/978-3-030-35723-8_8Dysthe M, Parihar R. Myeloid-Derived Suppressor Cells in the Tumor Microenvironment. Adv Exp Med Biol. 2020;1224:117–40. https://doi.org/10.1007/978-3-030-35723-8_8Iglesias-Escudero M, Arias-González N, Martínez-Cáceres E. Regulatory cells and the effect of cancer immunotherapy. Molecular Cancer. 2023;22:26. https://doi.org/10.1186/s12943-023-01714-0Iglesias-Escudero M, Arias-González N, Martínez-Cáceres E. Regulatory cells and the effect of cancer immunotherapy. Molecular Cancer. 2023;22:26. https://doi.org/10.1186/s12943-023-01714-0Shang J, Zha H, Sun Y. Phenotypes, Functions, and Clinical Relevance of Regulatory B Cells in Cancer. Front Immunol. 2020;11:582657. https://doi.org/10.3389/fimmu.2020.582657Shang J, Zha H, Sun Y. Phenotypes, Functions, and Clinical Relevance of Regulatory B Cells in Cancer. Front Immunol. 2020;11:582657. https://doi.org/10.3389/fimmu.2020.582657Zwirner NW, Domaica CI, Fuertes MB. Regulatory functions of NK cells during infections and cancer. Journal of Leukocyte Biology. 2021;109:185–94. https://doi.org/10.1002/JLB.3MR0820-685RZwirner NW, Domaica CI, Fuertes MB. Regulatory functions of NK cells during infections and cancer. Journal of Leukocyte Biology. 2021;109:185–94. https://doi.org/10.1002/JLB.3MR0820-685RZhang Z, Guo J, Jia R. Treg plasticity and human diseases. Inflamm Res. 2023;72:2181–97. https://doi.org/10.1007/s00011-023-01808-xZhang Z, Guo J, Jia R. Treg plasticity and human diseases. Inflamm Res. 2023;72:2181–97. https://doi.org/10.1007/s00011-023-01808-xЧуров АВ, Новицкая АВ, Жулай ГА. Иммунотерапия нового поколения: регуляторные T-клетки. Гены и клетки. 2021;16(3);16–32. https://doi.org/10.23868/202110003Churov AV, Novitskaya AV, Zhulay GA. Immunoterapiya novogo pokoleniya: regulyatornye T-kletki. Genes & cells. 2021;16(3);16–32. (In Russ.). https://doi.org/10.23868/202110003Blinova VG, Zhdanov DD. Many Faces of Regulatory T Cells: Heterogeneity or Plasticity? Cells. 2024;13:959. https://doi.org/10.3390/cells13110959Blinova VG, Zhdanov DD. Many Faces of Regulatory T Cells: Heterogeneity or Plasticity? Cells. 2024;13:959. https://doi.org/10.3390/cells13110959Wang J, Gong R, Zhao C, Lei K, Sun X, Ren H. Human FOXP3 and tumour microenvironment. Immunology. 2023;168:248–55. https://doi.org/10.1111/imm.13520Wang J, Gong R, Zhao C, Lei K, Sun X, Ren H. Human FOXP3 and tumour microenvironment. Immunology. 2023;168:248–55. https://doi.org/10.1111/imm.13520Sadlon T, Brown CY, Bandara V, Hope CM, Schjenken JE, Pederson SM, et al. Unravelling the molecular basis for regulatory T-cell plasticity and loss of function in disease. Clin Transl Immunology. 2018;7(2):1011. https://doi.org/10.1002/cti2.1011Sadlon T, Brown CY, Bandara V, Hope CM, Schjenken JE, Pederson SM, et al. Unravelling the molecular basis for regulatory T-cell plasticity and loss of function in disease. Clin Transl Immunology. 2018;7(2):1011. https://doi.org/10.1002/cti2.1011Glasner A, Plitas G. Tumor resident regulatory T cells. Semin Immunol. 2021;52:101476 https://doi.org/10.1016/j.smim.2021.101476Glasner A, Plitas G. Tumor resident regulatory T cells. Semin Immunol. 2021;52:101476 https://doi.org/10.1016/j.smim.2021.101476Liston A, Pasciuto E, Fitzgerald DC, Yshii L. Brain regulatory T cells. Nat Rev Immunol. 2024;24:326–37. https://doi.org/10.1038/s41577-023-00960-zListon A, Pasciuto E, Fitzgerald DC, Yshii L. Brain regulatory T cells. Nat Rev Immunol. 2024;24:326–37. https://doi.org/10.1038/s41577-023-00960-zRatnam NM, Gilbert MR, Giles AJ. Immunotherapy in CNS cancers: the role of immune cell trafficking. Neuro-Oncology. 2019;21:37–46. https://doi.org/10.1093/neuonc/noy084Ratnam NM, Gilbert MR, Giles AJ. Immunotherapy in CNS cancers: the role of immune cell trafficking. Neuro-Oncology. 2019;21:37–46. https://doi.org/10.1093/neuonc/noy084Richardson LG, Nieman LT, Stemmer-Rachamimov AO, Zheng XS, Stafford K, Nagashima H, et al. IDH-mutant gliomas harbor fewer regulatory T cells in humans and mice. Oncoimmunology. 2020;9:1806662. https://doi.org/10.1080/2162402X.2020.1806662Richardson LG, Nieman LT, Stemmer-Rachamimov AO, Zheng XS, Stafford K, Nagashima H, et al. IDH-mutant gliomas harbor fewer regulatory T cells in humans and mice. Oncoimmunology. 2020;9:1806662. https://doi.org/10.1080/2162402X.2020.1806662Panek WK, Toedebusch RG, Mclaughlin BE, Dickinson PJ, Van Dyke JE, Woolard KD, et al. The CCL2-CCR4 axis promotes Regulatory T cell trafficking to canine glioma tissues. J Neurooncol. 2024;169:647–58. https://doi.org/10.1007/s11060-024-04766-4Panek WK, Toedebusch RG, Mclaughlin BE, Dickinson PJ, Van Dyke JE, Woolard KD, et al. The CCL2-CCR4 axis promotes Regulatory T cell trafficking to canine glioma tissues. J Neurooncol. 2024;169:647–58. https://doi.org/10.1007/s11060-024-04766-4Canella A, Artomov M, Ukhatov A, Rajendran S, Perez P, Saini U, et al. Primary murine high-grade glioma cells derived from RCAS/tv-a diffuse glioma model reprogram naive T cells into immunosuppressive regulatory T lymphocytes. Mol Ther Oncol. 2024;32:200861. https://doi.org/10.1016/j.omton.2024.200861Canella A, Artomov M, Ukhatov A, Rajendran S, Perez P, Saini U, et al. Primary murine high-grade glioma cells derived from RCAS/tv-a diffuse glioma model reprogram naive T cells into immunosuppressive regulatory T lymphocytes. Mol Ther Oncol. 2024;32:200861. https://doi.org/10.1016/j.omton.2024.200861Crane CA, Ahn BJ, Han SJ, Parsa AT. Soluble factors secreted by glioblastoma cell lines facilitate recruitment, survival, and expansion of regulatory T cells: implications for immunotherapy. Neuro-Oncology. 2012;14:5:584–95. https://doi.org/10.1093/neuonc/nos014Crane CA, Ahn BJ, Han SJ, Parsa AT. Soluble factors secreted by glioblastoma cell lines facilitate recruitment, survival, and expansion of regulatory T cells: implications for immunotherapy. Neuro-Oncology. 2012;14:5:584–95. https://doi.org/10.1093/neuonc/nos014Dikiy S, Rudensky AY. Principles of regulatory T cell function. Immunity. 2023;56:240–55. https://doi.org/10.1016/j.immuni.2023.01.004Dikiy S, Rudensky AY. Principles of regulatory T cell function. Immunity. 2023;56:240–55. https://doi.org/10.1016/j.immuni.2023.01.004Lu L, Sun J, Su H, Luo S, Chen J, Qiu S, et al. Antitumor CD8 T cell responses in glioma patients are effectively suppressed by T follicular regulatory cells. Exp Cell Res. 2021;407:112808. https://doi.org/10.1016/j.yexcr.2021.112808Lu L, Sun J, Su H, Luo S, Chen J, Qiu S, et al. Antitumor CD8 T cell responses in glioma patients are effectively suppressed by T follicular regulatory cells. Exp Cell Res. 2021;407:112808. https://doi.org/10.1016/j.yexcr.2021.112808Luu Hoang KN, Anstee JE, Arnold JN. The Diverse Roles of Heme Oxygenase-1 in Tumor Progression. Front Immunol. 2021;12. https://doi.org/10.3389/fimmu.2021.658315Luu Hoang KN, Anstee JE, Arnold JN. The Diverse Roles of Heme Oxygenase-1 in Tumor Progression. Front Immunol. 2021;12. https://doi.org/10.3389/fimmu.2021.658315Zhdanov DD, Gladilina YA, Pokrovsky VS, Grishin DV, Grachev VA, Orlova VS, et al. Murine regulatory T cells induce death of effector T, B, and NK lymphocytes through a contact-independent mechanism involving telomerase suppression and telomereassociated senescence. Cell Immunol. 2018;331:146–60. https://doi.org/10.1016/j.cellimm.2018.06.008Zhdanov DD, Gladilina YA, Pokrovsky VS, Grishin DV, Grachev VA, Orlova VS, et al. Murine regulatory T cells induce death of effector T, B, and NK lymphocytes through a contact-independent mechanism involving telomerase suppression and telomereassociated senescence. Cell Immunol. 2018;331:146–60. https://doi.org/10.1016/j.cellimm.2018.06.008Liu S, Zhang C, Wang B, Zhang H, Qin G, Li C, et al. Regulatory T cells promote glioma cell stemness through TGF-β–NF-κB–IL6–STAT3 signaling. Cancer Immunol Immunother. 2021;70:2601–16. https://doi.org/10.1007/s00262-021-02872-0Liu S, Zhang C, Wang B, Zhang H, Qin G, Li C, et al. Regulatory T cells promote glioma cell stemness through TGF-β–NF-κB–IL6–STAT3 signaling. Cancer Immunol Immunother. 2021;70:2601–16. https://doi.org/10.1007/s00262-021-02872-0Wang Y, Huang T, Gu J, Lu L. Targeting the metabolism of tumor-infiltrating regulatory T cells. Trends in Immunology. 2023;44:598–612. https://doi.org/10.1016/j.it.2023.06.001Wang Y, Huang T, Gu J, Lu L. Targeting the metabolism of tumor-infiltrating regulatory T cells. Trends in Immunology. 2023;44:598–612. https://doi.org/10.1016/j.it.2023.06.001Chen B-J, Zhao J-W, Zhang D-H, Zheng A-H, Wu G-Q. Immunotherapy of Cancer by Targeting Regulatory T cells. Int Immunopharmacol. 2022;104:108469. https://doi.org/10.1016/j.intimp.2021.108469Chen B-J, Zhao J-W, Zhang D-H, Zheng A-H, Wu G-Q. Immunotherapy of Cancer by Targeting Regulatory T cells. Int Immunopharmacol. 2022;104:108469. https://doi.org/10.1016/j.intimp.2021.108469Wang AX, Ong XJ, D’Souza C, Neeson PJ, Zhu JJ. Combining chemotherapy with CAR-T cell therapy in treating solid tumors. Front Immunol. 2023;14. https://doi.org/10.3389/fimmu.2023.1140541Wang AX, Ong XJ, D’Souza C, Neeson PJ, Zhu JJ. Combining chemotherapy with CAR-T cell therapy in treating solid tumors. Front Immunol. 2023;14. https://doi.org/10.3389/fimmu.2023.1140541van Hooren L, Handgraaf SM, Kloosterman DJ, Karimi E, van Mil LWHG, Gassama AA, et al. CD103 + regulatory T cells underlie resistance to radio-immunotherapy and impair CD8 + T cell activation in glioblastoma. Nat Cancer. 2023;4:665–81. https://doi.org/10.1038/s43018-023-00547-6van Hooren L, Handgraaf SM, Kloosterman DJ, Karimi E, van Mil LWHG, Gassama AA, et al. CD103 + regulatory T cells underlie resistance to radio-immunotherapy and impair CD8 + T cell activation in glioblastoma. Nat Cancer. 2023;4:665–81. https://doi.org/10.1038/s43018-023-00547-6Peng Y, Tao Y, Zhang Y, Wang J, Yang J, Wang Y. CD25: A potential tumor therapeutic target. Int J Cancer. 2023;152:1290–303. https://doi.org/10.1002/ijc.34281Peng Y, Tao Y, Zhang Y, Wang J, Yang J, Wang Y. CD25: A potential tumor therapeutic target. Int J Cancer. 2023;152:1290–303. https://doi.org/10.1002/ijc.34281Buchan SL, Rogel A, Al-Shamkhani A. The immunobiology of CD27 and OX40 and their potential as targets for cancer immunotherapy. Blood. 2018;131:39–48. https://doi.org/10.1182/blood-2017-07-741025Buchan SL, Rogel A, Al-Shamkhani A. The immunobiology of CD27 and OX40 and their potential as targets for cancer immunotherapy. Blood. 2018;131:39–48. https://doi.org/10.1182/blood-2017-07-741025Muth S, Klaric A, Radsak M, Schild H, Probst HC. CD27 expression on Treg cells limits immune responses against tumors. J Mol Med (Berl). 2022;100:439–49. https://doi.org/10.1007/s00109-021-02116-9Muth S, Klaric A, Radsak M, Schild H, Probst HC. CD27 expression on Treg cells limits immune responses against tumors. J Mol Med (Berl). 2022;100:439–49. https://doi.org/10.1007/s00109-021-02116-9Li Q, Lu J, Li J, Zhang B, Wu Y, Ying T. Antibody-based cancer immunotherapy by targeting regulatory T cells. Front Oncol. 2023;13:1157345. https://doi.org/10.3389/fonc.2023.1157345Li Q, Lu J, Li J, Zhang B, Wu Y, Ying T. Antibody-based cancer immunotherapy by targeting regulatory T cells. Front Oncol. 2023;13:1157345. https://doi.org/10.3389/fonc.2023.1157345Zhulai G, Oleinik E. Targeting regulatory T cells in anti-PD-1/PD-L1 cancer immunotherapy. Scand J Immunol. 2022;95:13129. https://doi.org/10.1111/sji.13129Zhulai G, Oleinik E. Targeting regulatory T cells in anti-PD-1/PD-L1 cancer immunotherapy. Scand J Immunol. 2022;95:13129. https://doi.org/10.1111/sji.13129Arrieta VA, Dmello C, McGrail DJ, Brat DJ, Lee-Chang C, Heimberger AB, et al. Immune checkpoint blockade in glioblastoma: from tumor heterogeneity to personalized treatment. The Journal of Clinical Investigation. 2023;133:163447. https://doi.org/10.1172/JCI163447Arrieta VA, Dmello C, McGrail DJ, Brat DJ, Lee-Chang C, Heimberger AB, et al. Immune checkpoint blockade in glioblastoma: from tumor heterogeneity to personalized treatment. The Journal of Clinical Investigation. 2023;133:163447. https://doi.org/10.1172/JCI163447Yang T, Kong Z, Ma W. PD-1/PD-L1 immune checkpoint inhibitors in glioblastoma: clinical studies, challenges and potential. Hum Vaccin Immunother. 2021;17:546–53. https://doi.org/10.1080/21645515.2020.1782692Yang T, Kong Z, Ma W. PD-1/PD-L1 immune checkpoint inhibitors in glioblastoma: clinical studies, challenges and potential. Hum Vaccin Immunother. 2021;17:546–53. https://doi.org/10.1080/21645515.2020.1782692Badani A, Ozair A, Khasraw M, Woodworth GF, Tiwari P, Ahluwalia MS, et al. Immune checkpoint inhibitors for glioblastoma: emerging science, clinical advances, and future directions. J Neurooncol. 2025;171:531–47. https://doi.org/10.1007/s11060-024-04881-2Badani A, Ozair A, Khasraw M, Woodworth GF, Tiwari P, Ahluwalia MS, et al. Immune checkpoint inhibitors for glioblastoma: emerging science, clinical advances, and future directions. J Neurooncol. 2025;171:531–47. https://doi.org/10.1007/s11060-024-04881-2Whiteside SK, Grant FM, Alvisi G, Clarke J, Tang L, Imianowski CJ, et al. Acquisition of suppressive function by conventional T cells limits anti-tumor immunity upon Treg depletion. Sci Immunol. 2023;8:5558. https://doi.org/10.1126/sciimmunol.abo5558Whiteside SK, Grant FM, Alvisi G, Clarke J, Tang L, Imianowski CJ, et al. Acquisition of suppressive function by conventional T cells limits anti-tumor immunity upon Treg depletion. Sci Immunol. 2023;8:5558. https://doi.org/10.1126/sciimmunol.abo5558Li Y, Zhang C, Jiang A, Lin A, Liu Z, Cheng X, et al. Potential anti-tumor effects of regulatory T cells in the tumor microenvironment: a review. J Transl Med. 2024;22:293. https://doi.org/10.1186/s12967-024-05104-yLi Y, Zhang C, Jiang A, Lin A, Liu Z, Cheng X, et al. Potential anti-tumor effects of regulatory T cells in the tumor microenvironment: a review. J Transl Med. 2024;22:293. https://doi.org/10.1186/s12967-024-05104-yAmoozgar Z, Kloepper J, Ren J, Tay RE, Kazer SW, Kiner E, et al. Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas. Nat Commun. 2021;12:2582. https://doi.org/10.1038/s41467-021-22885-8Amoozgar Z, Kloepper J, Ren J, Tay RE, Kazer SW, Kiner E, et al. Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas. Nat Commun. 2021;12:2582. https://doi.org/10.1038/s41467-021-22885-8Panek WK, Pituch KC, Miska J, Kim JW, Rashidi A, Kanojia D, et al. Local Application of Autologous Platelet-Rich Fibrin Patch (PRF-P) Suppresses Regulatory T Cell Recruitment in a Murine Glioma Model. Mol Neurobiol. 2019;56:5032–40. https://doi.org/10.1007/s12035-018-1430-0Panek WK, Pituch KC, Miska J, Kim JW, Rashidi A, Kanojia D, et al. Local Application of Autologous Platelet-Rich Fibrin Patch (PRF-P) Suppresses Regulatory T Cell Recruitment in a Murine Glioma Model. Mol Neurobiol. 2019;56:5032–40. https://doi.org/10.1007/s12035-018-1430-0

The authors declare that there are no conflicts of interest present.