{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T06:00:25Z","timestamp":1785218425724,"version":"3.55.0"},"reference-count":82,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape for relapsed and refractory hematologic malignancies. However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains one of the most clinically significant and potentially life-threatening toxicities, limiting the broader applicability of this otherwise promising modality. Current standard-of-care (SOC) management of ICANS relies heavily on corticosteroids, which are not always effective and at high doses and with prolonged exposure may carry substantial risks for infectious complications, steroid-induced hyperglycemia, acute steroid myopathy, and steroid-induced psychosis. Steroid-sparing strategies are thus urgently needed. In this article, we emphasize the role of immune cell activation and mitochondrial dysfunction as a feedforward amplifier of neuroinflammation during ICANS and describe a structured framework for identifying and selecting mitochondrial-targeting drugs suitable for repurposing in ICANS prophylaxis and treatment. These agents are recommended based on mechanistic relevance, central nervous system bioavailability, oncological safety, and translational precedent. We apply this framework to generate a candidate landscape and highlight leflunomide as a prototype example. This work details leflunomide\u2019s dihydroorotate dehydrogenase-centered mitochondrial pharmacology, summarizes evidence from adjacent neuroinflammatory disease contexts, and outlines a proposed staged clinical evaluation pathway.<\/jats:p>","DOI":"10.3389\/fphar.2026.1896516","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T05:37:50Z","timestamp":1785217070000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Repurposing mitochondrial-targeting drugs for management of ICANS in CAR T-cell therapy: a novel steroid-sparing approach"],"prefix":"10.3389","volume":"17","author":[{"given":"Atena","family":"Zahedi","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy Practice, University of California Irvine","place":["Irvine, CA, United States"]},{"name":"Department of Anatomy and Neurobiology, University of California Irvine","place":["Irvine, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Onwodi V.","family":"Ifejeokwu","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurobiology, University of California Irvine","place":["Irvine, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn P.","family":"Griffin","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy Practice, University of California Irvine","place":["Irvine, CA, United States"]},{"name":"Hematopoietic Stem Cell Transplantation and Cellular Therapy Program, Division of Hematology\/Oncology, Department of Medicine, University of California Irvine","place":["Orange, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin A.","family":"Dean","sequence":"additional","affiliation":[{"name":"Hematopoietic Stem Cell Transplantation and Cellular Therapy Program, Division of Hematology\/Oncology, Department of Medicine, University of California Irvine","place":["Orange, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1321","DOI":"10.1186\/s12967-025-07392-4","article-title":"Mitochondrial dysfunction acts as a modulator of the immunometabolic route for activating the cytosolic DNA sensor pathway in triggering innate immunosurveillance","volume":"23","author":"Algieri","year":"2025","journal-title":"J. Transl. Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"3414","DOI":"10.1016\/j.celrep.2017.11.079","article-title":"Extracellular ATP activates the NLRP3 inflammasome and is an early danger signal of skin allograft rejection","volume":"21","author":"Amores-Iniesta","year":"2017","journal-title":"Cell Rep."},{"key":"B4","volume-title":"Expert: FDA Approves Tocilizumab-Anoh as a Biosimilar to Actemra | Pharmacy Times","author":"Associate","year":"2026"},{"key":"B5","volume-title":"Official HCP Website. Avtozma","year":"2024"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1739021","DOI":"10.3389\/fneur.2026.1739021","article-title":"Immune effector cell-associated neurotoxicity syndrome: integrative mechanisms, predictive biomarkers, and translational pathways for prevention in CAR T-cell therapy","volume":"17","author":"Aziz","year":"2026","journal-title":"Front. Neurol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1007\/s13300-023-01393-6","article-title":"Practical guide to glucocorticoid induced hyperglycaemia and diabetes","volume":"14","author":"Barker","year":"2023","journal-title":"Diabetes Ther."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.825816","article-title":"Astrocytes as key regulators of brain energy metabolism: new therapeutic perspectives","volume":"12","author":"Beard","year":"2022","journal-title":"Front. Physiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e209928","DOI":"10.1212\/WNL.0000000000209928","article-title":"What is the role of cytokines in synaptic transmission?","volume":"103","author":"Benarroch","year":"2024","journal-title":"Neurology"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e008975","DOI":"10.1136\/jitc-2024-008975","article-title":"Bendamustine is a safe and effective lymphodepletion agent for axicabtagene ciloleucel in patients with refractory or relapsed large B-cell lymphoma","volume":"12","author":"Bharadwaj","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"B11","doi-asserted-by":"publisher","first-page":"9573","DOI":"10.1073\/pnas.160099797","article-title":"Inhibition of IL-2-induced Jak-STAT signaling by glucocorticoids","volume":"97","author":"Bianchi","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1546","DOI":"10.1016\/j.cmet.2021.07.006","article-title":"Astrocyte-neuron metabolic cooperation shapes brain activity","volume":"33","author":"Bonvento","year":"2021","journal-title":"Cell Metab."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1322","DOI":"10.4103\/NRR.NRR-D-24-01459","article-title":"Mitochondrial damage-associated molecular patterns: neuroimmunomodulators in central nervous system pathophysiology","volume":"21","author":"Brooks","year":"2026","journal-title":"Neural Regen. Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1038\/s41571-024-00903-0","article-title":"Current understanding and management of CAR T cell-associated toxicities","volume":"21","author":"Brudno","year":"2024","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"B3","unstructured":"Anticytokine therapy and corticosteroids for cytokine release syndrome and for neurotoxicity following T-Cell engager or CAR T-Cell therapy: rapid review. Canadian agency for drugs and technologies in health\n          \n          \n          2026"},{"key":"B15","doi-asserted-by":"publisher","first-page":"S222","DOI":"10.1016\/j.jtct.2023.12.289","article-title":"Bendamustine-Containing regimens before CAR T-Cell therapy have detrimental effect on progression-free survival","volume":"30","author":"Chahine","year":"2024","journal-title":"Transplant. Cell. Ther."},{"key":"B16","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1186\/s12974-016-0710-8","article-title":"Infliximab reduces peripheral inflammation, neuroinflammation, and extracellular GABA in the cerebellum and improves learning and motor coordination in rats with hepatic encephalopathy","volume":"13","author":"Dadsetan","year":"2016","journal-title":"J. Neuroinflammation"},{"key":"B17","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.psym.2011.12.007","article-title":"The neuropsychiatric complications of glucocorticoid use: steroid psychosis revisited","volume":"53","author":"Dubovsky","year":"2012","journal-title":"Psychosomatics"},{"key":"B18","doi-asserted-by":"publisher","first-page":"3047","DOI":"10.4049\/jimmunol.1701723","article-title":"Cutting edge: mitochondrial assembly of the NLRP3 inflammasome complex is initiated at priming","volume":"200","author":"Elliott","year":"2018","journal-title":"J. Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e123","DOI":"10.1016\/j.bbmt.2018.12.756","article-title":"Cytokine release syndrome with chimeric antigen receptor T cell therapy","volume":"25","author":"Frey","year":"2019","journal-title":"Biol. Blood Marrow Transpl."},{"key":"B20","doi-asserted-by":"publisher","first-page":"28","DOI":"10.14740\/jmc5211","article-title":"Cyclophosphamide for the treatment of refractory immune effector cell-associated neurotoxicity syndrome following CD19-Targeted CAR T-Cell therapy","volume":"17","author":"Frisch","year":"2026","journal-title":"J. Med. Cases"},{"key":"B21","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1111\/bjh.18596","article-title":"Endothelial activation predicts disseminated intravascular coagulopathy, cytokine release syndrome and prognosis in patients treated with anti-CD19 CAR-T cells","volume":"201","author":"Galli","year":"2023","journal-title":"Br. J. Haematol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/s41591-018-0041-7","article-title":"CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade","volume":"24","author":"Giavridis","year":"2018","journal-title":"Nat. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1186\/s40425-018-0371-5","article-title":"Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy","volume":"6","author":"Giles","year":"2018","journal-title":"J. Immunother. Cancer"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1832","DOI":"10.1016\/j.bbmt.2019.04.028","article-title":"Use of leflunomide for treatment of cytomegalovirus infection in recipients of allogeneic stem cell transplant","volume":"25","author":"Gokarn","year":"2019","journal-title":"Biol. Blood Marrow Transpl."},{"key":"B25","doi-asserted-by":"publisher","first-page":"e1576","DOI":"10.1002\/wsbm.1576","article-title":"Mechanisms of immune effector cell-associated neurotoxicity syndrome after CAR-T treatment","volume":"14","author":"Gu","year":"2022","journal-title":"WIREs Mech. Dis."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1404","DOI":"10.1158\/2159-8290.CD-17-0698","article-title":"Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells","volume":"7","author":"Gust","year":"2017","journal-title":"Cancer Discov."},{"key":"B27","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1111\/j.1365-2141.1987.tb06136.x","article-title":"Anti-granulocyte opsonic activity in sera from patients with systemic lupus erythematosus","volume":"65","author":"Hadley","year":"1987","journal-title":"Br. J. Haematol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e70463","DOI":"10.1111\/ejn.70463","article-title":"Mobile powerhouses: Mitochondria transfer via tunnelling nanotubes in brain health and neurodegenerative diseases","volume":"63","author":"Henrich","year":"2026","journal-title":"Eur. J. Neurosci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"11063","DOI":"10.1111\/jcmm.17029","article-title":"Predictive role of endothelial cell activation in cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukaemia","volume":"25","author":"Hong","year":"2021","journal-title":"J. Cell Mol. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"2430","DOI":"10.1182\/blood.2022017414","article-title":"How I treat refractory CRS and ICANS after CAR T-cell therapy","volume":"141","author":"Jain","year":"2023","journal-title":"Blood"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1038\/s12276-021-00649-0","article-title":"Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms","volume":"53","author":"Kang","year":"2021","journal-title":"Exp. Mol. Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1380451","DOI":"10.3389\/fimmu.2024.1380451","article-title":"Case report: rapid resolution of grade IV ICANS after first line intrathecal chemotherapy with methotrexate, cytarabine and dexamethasone","volume":"15","author":"Katsin","year":"2024","journal-title":"Front. Immunol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1038\/s41571-019-0258-5","article-title":"TKI-Based on\/off switch for CAR T cells","volume":"16","author":"Killock","year":"2019","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1038\/s12276-023-00965-7","article-title":"Molecular mechanisms of mitochondrial DNA release and activation of the cGAS-STING pathway","volume":"55","author":"Kim","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"877477","DOI":"10.3389\/fimmu.2022.877477","article-title":"EASIX and severe endothelial complications after CD19-Directed CAR-T cell Therapy-A cohort study","volume":"13","author":"Korell","year":"2022","journal-title":"Front. Immunol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1084\/jem.188.4.619","article-title":"Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes","volume":"188","author":"Krause","year":"1998","journal-title":"J. Exp. Med."},{"key":"B37","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/s40478-023-01526-9","article-title":"Roles of neuropathology-associated reactive astrocytes: a systematic review","volume":"11","author":"Lawrence","year":"2023","journal-title":"Acta Neuropathol. Commun."},{"key":"B38","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1634\/theoncologist.2018-0028","article-title":"FDA approval summary: Tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome","volume":"23","author":"Le","year":"2018","journal-title":"Oncologist"},{"key":"B39","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1016\/j.bbmt.2018.12.758","article-title":"ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells","volume":"25","author":"Lee","year":"2019","journal-title":"Biol. Blood Marrow Transpl."},{"key":"B40","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.neuroscience.2021.11.001","article-title":"Etanercept reduces neuron injury and neuroinflammation via inactivating c-Jun N-terminal kinase and nuclear Factor-\u03baB pathways in alzheimer\u2019s disease: an in vitro and in vivo investigation","volume":"484","author":"Li","year":"2022","journal-title":"Neuroscience"},{"key":"B41","doi-asserted-by":"publisher","first-page":"2418","DOI":"10.1002\/glia.24433","article-title":"Knockout of microglial Hv1 proton channel reduces neurotoxic A1 astrocytes and neuronal damage via the ROS\/STAT3 pathway after spinal cord injury","volume":"71","author":"Li","year":"2023","journal-title":"Glia"},{"key":"B42","doi-asserted-by":"publisher","first-page":"e70066","DOI":"10.1002\/cbf.70066","article-title":"The mechanisms and implications of cardiolipin in the regulation of cell death","volume":"43","author":"Li","year":"2025","journal-title":"Cell Biochem. Funct."},{"key":"B43","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1038\/s41467-019-13668-3","article-title":"Mitochondrial TCA cycle metabolites control physiology and disease","volume":"11","author":"Mart\u00ednez-Reyes","year":"2020","journal-title":"Nat. Commun."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1716317","DOI":"10.3389\/fimmu.2025.1716317","article-title":"Early intrathecal dexamethasone and methotrexate as an effective approach for immune effector cell-associated neurotoxicity syndrome after CAR-T cell therapies","volume":"16","author":"Meng","year":"2025","journal-title":"Front. Immunol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"eaau5907","DOI":"10.1126\/scitranslmed.aau5907","article-title":"The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on\/off switch for CAR T cells","volume":"11","author":"Mestermann","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/j.cell.2016.08.064","article-title":"Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages","volume":"167","author":"Mills","year":"2016","journal-title":"Cell"},{"key":"B47","doi-asserted-by":"publisher","first-page":"3904","DOI":"10.3390\/ijms26083904","article-title":"Intravenous Immunoglobulin (IVIG) for patients with severe neurotoxicity associated with chimeric antigen receptor T-Cell (CAR-T) therapy","volume":"26","author":"Mokhtari","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1007\/s11481-011-9287-2","article-title":"Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system","volume":"7","author":"Montgomery","year":"2012","journal-title":"J. Neuroimmune Pharmacol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1038\/s41573-024-01100-5","article-title":"Novel strategies to manage CAR-T cell toxicity","volume":"24","author":"Mulvey","year":"2025","journal-title":"Nat. Rev. Drug Discov."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1002\/glia.23587","article-title":"Lipopolysaccharide-induced alteration of mitochondrial morphology induces a metabolic shift in microglia modulating the inflammatory response in vitro and in vivo","volume":"67","author":"Nair","year":"2019","journal-title":"Glia"},{"key":"B51","unstructured":"PubChem compound summary for CID 54684141, teriflunomide\n          \n          \n          2026"},{"key":"B52","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1146\/annurev.immunol.26.021607.090232","article-title":"Anti-inflammatory actions of intravenous immunoglobulin","volume":"26","author":"Nimmerjahn","year":"2008","journal-title":"Annu. Rev. Immunol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1038\/s41591-018-0036-4","article-title":"Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells","volume":"24","author":"Norelli","year":"2018","journal-title":"Nat. Med."},{"key":"B54","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1111\/bjh.17527","article-title":"Prophylactic corticosteroid use in patients receiving axicabtagene ciloleucel for large B-cell lymphoma","volume":"194","author":"Oluwole","year":"2021","journal-title":"Br. J. Haematol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"861231","DOI":"10.1155\/2014\/861231","article-title":"Tumor necrosis factor alpha: a link between neuroinflammation and excitotoxicity","volume":"2014","author":"Olmos","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"B56","doi-asserted-by":"publisher","first-page":"S31","DOI":"10.1016\/j.healun.2014.01.114","article-title":"Successful use of cidofovir and leflunomide in lung transplant recipient with BK polyomavirus encephalitis","volume":"33","author":"Ong","year":"2014","journal-title":"J. Heart Lung Transplant."},{"key":"B57","doi-asserted-by":"publisher","first-page":"1710","DOI":"10.1038\/s41591-023-02404-6","article-title":"CD19 CAR T-cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: phase 2 trial interim results","volume":"29","author":"Park","year":"2023","journal-title":"Nat. Med."},{"key":"B58","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/s41586-024-07167-9","article-title":"Mitochondrial complex I activity in microglia sustains neuroinflammation","volume":"628","author":"Peruzzotti-Jametti","year":"2024","journal-title":"Nature"},{"key":"B59","doi-asserted-by":"publisher","first-page":"892","DOI":"10.1016\/j.tcb.2020.09.004","article-title":"Cardiolipin in immune signaling and cell death","volume":"30","author":"Pizzuto","year":"2020","journal-title":"Trends Cell Biol."},{"key":"B60","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1007\/978-1-4612-1610-0_24","article-title":"Mechanisms of action of intravenous Immunoglobulin (IVIg) in immune-mediated diseases","volume-title":"Autoimmune Reactions","author":"Prasad","year":"1999"},{"key":"B61","doi-asserted-by":"publisher","first-page":"47","DOI":"10.3892\/ijmm.2024.5371","article-title":"Mitochondrial dysfunction in chronic neuroinflammatory diseases","volume":"53","author":"Qin","year":"2024","journal-title":"Int. J. Mol. Med."},{"key":"B62","doi-asserted-by":"publisher","first-page":"5430","DOI":"10.1074\/jbc.AC119.007558","article-title":"Granulocyte-macrophage colony-stimulating factor inactivation in CAR T-cells prevents monocyte-dependent release of key cytokine release syndrome mediators","volume":"294","author":"Sachdeva","year":"2019","journal-title":"J. Biol. Chem."},{"key":"B63","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1038\/nri3401","article-title":"Intravenous immunoglobulin therapy: how does IgG modulate the immune system?","volume":"13","author":"Schwab","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"B64","doi-asserted-by":"publisher","first-page":"2148","DOI":"10.1007\/s11064-013-1123-z","article-title":"Reactive oxygen species from human astrocytes induced functional impairment and oxidative damage","volume":"38","author":"Sheng","year":"2013","journal-title":"Neurochem. Res."},{"key":"B65","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1182\/blood-2018-10-881722","article-title":"GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts","volume":"133","author":"Sterner","year":"2019","journal-title":"Blood"},{"key":"B66","doi-asserted-by":"publisher","first-page":"1450173","DOI":"10.3389\/fimmu.2024.1450173","article-title":"Identification of early predictive biomarkers for severe cytokine release syndrome in pediatric patients with chimeric antigen receptor T-cell therapy","volume":"15","author":"Su","year":"2024","journal-title":"Front. Immunol."},{"key":"B67","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1038\/nri856","article-title":"Roles of Fc receptors in autoimmunity","volume":"2","author":"Takai","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1038\/nature11986","article-title":"Succinate is an inflammatory signal that induces IL-1\u03b2 through HIF-1\u03b1","volume":"496","author":"Tannahill","year":"2013","journal-title":"Nature"},{"key":"B69","doi-asserted-by":"publisher","first-page":"e24029","DOI":"10.1016\/j.heliyon.2024.e24029","article-title":"Advances in crosstalk among innate immune pathways activated by mitochondrial DNA","volume":"10","author":"Tao","year":"2024","journal-title":"Heliyon"},{"key":"B70","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1016\/j.jtct.2024.10.005","article-title":"Cautionary tale of unopposed prophylactic IL6 receptor blockade in axicabtagene ciloleucel for large B-Cell lymphoma","volume":"30","author":"Valtis","year":"2024","journal-title":"Transpl. Cell Ther."},{"key":"B71","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1007\/s12288-018-0929-x","article-title":"Leflunomide: is it the game changer in musculoskeletal chronic graft Versus host disease?","volume":"34","author":"Vijaysekharan","year":"2018","journal-title":"Indian J. Hematol. Blood Transfus."},{"key":"B72","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1038\/s43018-024-00764-7","article-title":"Targeting TGF\u03b2-activated kinase-1 activation in microglia reduces CAR T immune effector cell-associated neurotoxicity syndrome","volume":"5","author":"Vinnakota","year":"2024","journal-title":"Nat. Cancer"},{"key":"B73","doi-asserted-by":"publisher","first-page":"100027","DOI":"10.1016\/j.bict.2025.100027","article-title":"In vivo generation of CAR T cells: biology, delivery platforms, clinical promise, and translational challenges","volume":"2","author":"Volta","year":"2026","journal-title":"Blood Immunol. and Cell. Ther"},{"key":"B74","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1038\/s41419-025-07454-x","article-title":"CAR-T therapy dilemma and innovative design strategies for next generation","volume":"16","author":"Wang","year":"2025","journal-title":"Cell Death Dis."},{"key":"B75","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1182\/bloodadvances.2018028720","article-title":"Pharmacologic control of CAR-T cell function using dasatinib","volume":"3","author":"Weber","year":"2019","journal-title":"Blood Adv."},{"key":"B76","doi-asserted-by":"publisher","first-page":"1904","DOI":"10.1016\/j.immuni.2025.07.012","article-title":"Mitochondria reactive oxygen species signaling-dependent immune responses in macrophages and T cells","volume":"58","author":"Weinberg","year":"2025","journal-title":"Immunity"},{"key":"B77","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1016\/j.immuni.2022.06.007","article-title":"Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-Dependent channels to activate NLRP3 inflammasome and interferon signaling","volume":"55","author":"Xian","year":"2022","journal-title":"Immunity"},{"key":"B78","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1186\/s13046-021-02148-6","article-title":"Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies","volume":"40","author":"Xiao","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"B79","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1016\/j.exer.2007.06.013","article-title":"Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells","volume":"85","author":"Yang","year":"2007","journal-title":"Exp. Eye Res."},{"key":"B80","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/s41421-021-00255-4","article-title":"CRISPR-Edited CART with GM-CSF knockout and auto secretion of IL6 and IL1 blockers in patients with hematologic malignancy","volume":"7","author":"Yi","year":"2021","journal-title":"Cell Discov."},{"key":"B81","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s13064-025-00223-8","article-title":"A review of mitochondrial dysfunction, pathophysiology and therapeutic prospects in neurodegenerative diseases","volume":"20","author":"Yusuf","year":"2025","journal-title":"Discov. Neurosci."},{"key":"B82","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1182\/bloodadvances.2024014027","article-title":"EASIX and m-EASIX predict CRS and ICANS in pediatric and AYA patients after CD19-CAR T-cell therapy","volume":"9","author":"Zandaki","year":"2025","journal-title":"Blood Adv."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1896516\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T05:37:52Z","timestamp":1785217072000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1896516\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,28]]},"references-count":82,"alternative-id":["10.3389\/fphar.2026.1896516"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1896516","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,28]]},"article-number":"1896516"}}