From tumor immunotherapy to myocardial injury: A mechanistic discussion of immune checkpoint inhibitor‑related myocarditis (Review)

Liu X, Hogg GD and DeNardo DG: Rethinking immune checkpoint blockade: ‘Beyond the T cell’. J Immunother Cancer. 9:e0014602021. View Article : Google Scholar

Blank C, Gajewski TF and Mackensen A: Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: Implications for tumor immunotherapy. Cancer Immunol Immunother. 54:307–314. 2005. View Article : Google Scholar

Naimi A, Mohammed RN, Raji A, Chupradit S, Yumashev AV, Suksatan W, Shalaby MN, Thangavelu L, Kamrava S, Shomali N, et al: Tumor immunotherapies by immune checkpoint inhibitors (ICIs); the pros and cons. Cell Commun Signal. 20:442022. View Article : Google Scholar

Korman AJ, Garrett-Thomson SC and Lonberg N: The foundations of immune checkpoint blockade and the ipilimumab approval decennial. Nat Rev Drug Discov. 21:509–528. 2022. View Article : Google Scholar

Wei J, Li W, Zhang P, Guo F and Liu M: Current trends in sensitizing immune checkpoint inhibitors for cancer treatment. Mol Cancer. 23:2792024. View Article : Google Scholar

Cone EB, Haeuser L and Reese SW: Immune checkpoint inhibitor monotherapy is associated with less cardiac toxicity than combination therapy. PLoS One. 17:e02720222022. View Article : Google Scholar

Salem JE, Manouchehri A, Moey M, Lebrun-Vignes B, Bastarache L, Pariente A, Gobert A, Spano JP, Balko JM, Bonaca MP, et al: Cardiovascular toxicities associated with immune checkpoint inhibitors: An observational, retrospective, pharmacovigilance study. Lancet Oncol. 19:1579–1589. 2018. View Article : Google Scholar

Gougis P, Jochum F, Abbar B, Dumas E, Bihan K, Lebrun-Vignes B, Moslehi J, Spano J, Laas E, Hotton J, et al: Clinical spectrum and evolution of immune-checkpoint inhibitors toxicities over a decade-a worldwide perspective. EClinicalMedicine. 70:1025362024. View Article : Google Scholar

Hu JR, Florido R, Lipson EJ, Naidoo J, Ardehali R, Tocchetti CG, Lyon AR, Padera RF, Johnson DB and Moslehi J: Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc Res. 115:854–868. 2019. View Article : Google Scholar

Yousif LI, Screever EM, Versluis D, Aboumsallem JP, Nierkens S, Manintveld OC, de Boer RA and Meijers WC: Risk factors for immune checkpoint inhibitor-mediated cardiovascular toxicities. Curr Oncol Rep. 25:753–763. 2023. View Article : Google Scholar

Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, Sullivan RJ, Damrongwatanasuk R, Chen CL, Gupta D, et al: Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol. 71:1755–1764. 2018. View Article : Google Scholar

Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B and Johnson DB: Increased reporting of fatal immune checkpoint Inhibitor-associated myocarditis. Lancet. 391:9332018. View Article : Google Scholar

Wang F, Sun X, Qin S, Hua H, Liu X, Yang L and Yang M: A retrospective study of immune checkpoint inhibitor-associated myocarditis in a single center in China. Cancer Commun. 9:162020.

Wang F, Qin S, Lou F, Chen FX, Shi M, Liang X, Jiang H, Jiang Y, Chen Y, Du Y, et al: Retrospective analysis of immune checkpoint Inhibitor-associated myocarditis from 12 cancer centers in China. J Clin Oncol. 38:e151302020. View Article : Google Scholar

Oren O, Yang EH, Molina JR, Bailey KR, Blumenthal RS and Kopecky SL: Cardiovascular health and outcomes in cancer patients receiving immune checkpoint inhibitors. Am J Cardiol. 125:1920–1926. 2020. View Article : Google Scholar

Fenioux C, Abbar B, Boussouar S, Bretagne M, Power JR, Moslehi JJ, Gougis P, Amelin D, Dechartres A, Lehmann LH, et al: Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis. Nat Med. 29:3100–3110. 2023. View Article : Google Scholar

Shelly S, Agmon-Levin N, Altman A and Shoenfeld Y: Thymoma and autoimmunity. Cell Mol Immunol. 8:199–202. 2011. View Article : Google Scholar

Zamami Y, Niimura T, Okada N, Koyama T, Fukushima K, Izawa-Ishizawa Y and Ishizawa K: Factors associated with immune checkpoint inhibitor-related myocarditis. JAMA Oncol. 5:1635–1637. 2019. View Article : Google Scholar

Puzanov I, Subramanian P, Yatsynovich YV, Jacobs DM, Chilbert MR, Sharma UC, Ito F, Feuerstein SG, Stefanovic F, Hicar MD, et al: Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis. J Immunother Cancer. 9:e0025532021. View Article : Google Scholar

Bonaca MP, Olenchock BA, Salem JE, Wiviott SD, Ederhy S, Cohen A, Stewart GC, Choueiri TK, Di Carli M, Kumbhani DJ, et al: Myocarditis in the setting of cancer therapeutics: Proposed case definitions for emerging clinical syndromes in Cardio-oncology. Circulation. 140:80–91. 2019. View Article : Google Scholar

Lehmann LH, Heckmann MB, Bailly G, Finke D, Procureur A, Power JR, Stein F, Bretagne M, Ederhy S, Moslehi J, et al: Cardiomuscular biomarkers in the diagnosis and prognostication of immune checkpoint inhibitor myocarditis. Circulation. 148:473–486. 2023. View Article : Google Scholar

Barac A, Wadlow RC, Deeken JF and deFilippi C: Cardiac troponin I and T in ICI myocarditis screening, diagnosis, and prognosis. J Am Coll Cardiol. 6:804–807. 2024.

Zotova L: Immune checkpoint Inhibitors-related myocarditis: A review of reported clinical cases. Diagnostics. 13:12432023. View Article : Google Scholar

Vasbinder A, Chen Y, Procureur A, Gradone A, Azam TU, Perry D, Shadid H, Anderson E, Catalan T, Blakely P, et al: Biomarker trends, incidence, and outcomes of immune checkpoint Inhibitor-induced myocarditis. JACC CardioOncol. 4:689–700. 2022. View Article : Google Scholar

Caio G: Myocarditis with immune checkpoint blockade. N Engl J Med. 376:291–292. 2017.

Semeraro GC, Cipolla CM and Cardinale DM: Role of cardiac biomarkers in cancer patients. Cancers (Basel). 13:54262021. View Article : Google Scholar

Song W, Zheng Y, Dong M, Zhong L, Bazoukis G, Perone F, Li G, Ng CF, Baranchuk A, Tse G and Liu T: Electrocardiographic features of immune checkpoint inhibitor-associated myocarditis. Curr Probl Cardiol. 48:1014782023. View Article : Google Scholar

Faron A, Isaak A, Mesropyan N, Reinert M, Schwab K, Sirokay J, Sprinkart AM, Bauernfeind FG, Dabir D, Pieper CC, et al: Cardiac MRI depicts immune checkpoint Inhibitor-induced myocarditis: A prospective study. Radiology. 301:602–609. 2021. View Article : Google Scholar

Correction to. Routine application of cardiac magnetic resonance imaging in patients with suspected myocarditis from immune checkpoint inhibitor therapy. Eur Heart J. 46:3042025. View Article : Google Scholar

Pereyra M, Farina J, Mahmoud AK, Scalia I, Tagle-Cornell MC, Kenyon C, Abbas MT, Baba N, Herrmann J, Arsanjani R and Ayoub C: The prognostic value of criteria for diagnosis of Immune Checkpoint Inhibitor Related Myocarditis: A comparison of the Bonaca et al. Criteria and European Society of Cardiology (ESC)-International Cardio-Oncology Society (ICOS) guidelines. Circulation. 150 (Suppl 1):A41420442024. View Article : Google Scholar

Salem JE, Bretagne M, Abbar B, Leonard-Louis S, Ederhy S, Redheuil A, Boussouar S, Nguyen LS, Procureur A, Stein F, et al: Abatacept/Ruxolitinib and screening for concomitant respiratory muscle failure to mitigate fatality of Immune-checkpoint inhibitor myocarditis. Cancer Discov. 13:1100–1115. 2023. View Article : Google Scholar

Thibault C, Vano Y, Soulat G and Mirabel M: Immune checkpoint inhibitors myocarditis: Not all cases are clinically patent. Eur Heart J. 39:35532018.

Domen H, Kaga K, Hida Y, Honma N, Kubota R, Yagi Y and Matsui Y: Investigation of lung cancer patients with cardiovascular disease. Kyobu Geka. 68:266–70. 2015.(In Japanese).

Murtagh G, deFilippi C, Zhao Q and Barac A: Circulating biomarkers in the diagnosis and prognosis of immune checkpoint inhibitor-related myocarditis: Time for a risk-based approach. Front Cardiovasc Med. 11:13505852024. View Article : Google Scholar

Palaskas N, Lopez-Mattei J, Durand JB, Iliescu C and Deswal A: Immune checkpoint inhibitor myocarditis: Pathophysiological characteristics, diagnosis, and treatment. J Am Heart Assoc. 9:e0137572020. View Article : Google Scholar

Pi JK, Chen XT, Zhang YJ, Chen XM, Wang YC, Xu JY, Zhou JH, Yu SS and Wu SS: Insight of immune checkpoint inhibitor related myocarditis. Int Immunopharmacol. 143:1135592024. View Article : Google Scholar

Heilbroner SP, Few R, Mueller J, Chalwa J, Charest F, Suryadevara S, Kratt C, Gomez-Caminero A and Dreyfus B: Predicting cardiac adverse events in patients receiving immune checkpoint inhibitors: A machine learning approach. J Immunother Cancer. 9:e0025452021. View Article : Google Scholar

Zhang C, Bockman A and DuPage M: Breaking up the CD8+ T cell: Treg pas de deux. Cell Mol Immunol. 42:941–942. 2024.

Yu L, Sun M, Zhang Q, Zhou Q and Wang Y: Harnessing the immune system by targeting immune checkpoints: Providing new hope for oncotherapy. Front Immunol. 13:9820262022. View Article : Google Scholar

Keir ME, Butte MJ, Freeman GJ and Sharpe AH: PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 26:677–704. 2008. View Article : Google Scholar

Boussiotis VA: Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med. 375:1767–1778. 2016. View Article : Google Scholar

Yi M, Zheng X, Niu M, Zhu S, Ge H and Wu K: Combination strategies with PD-1/PD-L1 blockade: Current advances and future directions. Mol Cancer. 21:282022. View Article : Google Scholar

Gaikwad S, Agrawal MY, Kaushik I, Ramachandran S and Srivastava SK: Immune checkpoint proteins: Signaling mechanisms and molecular interactions in cancer immunotherapy. Semin Cancer Biol. 86:137–150. 2022. View Article : Google Scholar

Malmberg R, Zietse M, Dumoulin DW, Hendrikx JJMA, Aerts JGJVA, van der Veldt AAM, Koch BCP, Sleijfer S, van Leeuwen RWF, Koch BCP, et al: Alternative dosing strategies for immune checkpoint inhibitors to improve cost-effectiveness: A special focus on nivolumab and pembrolizumab. Lancet Oncol. 23:e552–e561. 2022. View Article : Google Scholar

Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, et al: Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 377:1345–1356. 2017. View Article : Google Scholar

Xu D, Wang H, Bao Q, Jin K, Liu M, Liu W, Yan X, Wang L, Zhang Y, Wang G, et al: The anti-PD-L1/CTLA-4 bispecific antibody KN046 plus lenvatinib in advanced unresectable or metastatic hepatocellular carcinoma: A phase II trial. Nat Commun. 16:14432025. View Article : Google Scholar

Schaub J and Tang SC: Beyond checkpoint inhibitors: The three generations of immunotherapy. Clin Exp Med. 25:432025. View Article : Google Scholar

Buehning F, Lerchner T, Vogel J, Hendgen-Cotta UB, Totzeck M, Rassaf T and Michel L: Preclinical models of cardiotoxicity from immune checkpoint inhibitor therapy. Basic Res Cardiol. 120:171–185. 2025. View Article : Google Scholar

Wu MM, Yang YC, Cai YX, Jiang S, Xiao H, Miao C, Jin XY, Sun Y, Bi X, Hong Z, et al: Anti-CTLA-4 m2a antibody exacerbates cardiac injury in experimental autoimmune myocarditis mice by promoting Ccl5-Neutrophil infiltration. Adv Sci. 11:e24004862024. View Article : Google Scholar

Shang AQ, Yu CJ, Bi X, Jiang WW, Zhao ML, Sun Y, Guan H and Zhang ZR: Blocking CTLA-4 promotes pressure Overload-induced heart failure via activating Th17 cells. FASEB J. 38:e238512024. View Article : Google Scholar

Hossen MM, Ma Y, Yin Z, Xia Y, Du J, Huang JY, Huang JJ, Zou L, Ye Z and Huang Z: Current understanding of CTLA-4: From mechanism to autoimmune diseases. Front Immunol. 14:11983652023. View Article : Google Scholar

Maurer MF, Lewis KE, Kuijper JL, Ardourel D, Gudgeon CJ, Chandrasekaran S, Mudri SL, Kleist KN, Navas C, Wolfson MF, et al: The engineered CD80 variant fusion therapeutic davoceticept combines checkpoint antagonism with conditional CD28 costimulation for anti-tumor immunity. Nat Commun. 13:17902022. View Article : Google Scholar

Wang J, Sanmamed MF, Datar I, Su TT, Ji L, Sun J, Chen L, Chen Y, Zhu G, Yin W, et al: Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell. 176:334–347.e12. 2019. View Article : Google Scholar

Cillo AR, Cardello C, Shan F, Karapetyan L, Kunning S, Sander C, Rush E, Karunamurthy A, Massa RC, Rohatgi A, et al: Blockade of LAG-3 and PD-1 leads to Co-Expression of cytotoxic and exhaustion gene modules in CD8+ T cells to promote antitumor immunity. Cell. 187:4373–4388.e15. 2024. View Article : Google Scholar

Andrews LP, Butler SC, Cui J, Cillo AR, Cardello C, Liu C, Brunazzi EA, Baessler A, Xie B, Kunning SR, et al: LAG-3 and PD-1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN-γ-dependent anti-tumor immunity. Cell. 187:4355–4372.e22. 2024. View Article : Google Scholar

Sordo-Bahamonde C, Lorenzo-Herrero S, González-Rodríguez AP, Payer AR, González-García E, López-Soto A and Gonzalez S: LAG-3 Blockade with Relatlimab (BMS-986016) restores Anti-leukemic responses in chronic lymphocytic leukemia. Cancers (Basel). 13:21122021. View Article : Google Scholar

Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Gutiérrez EC, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, et al: Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 386:24–34. 2022. View Article : Google Scholar

Schwartz RH: Historical overview of immunological tolerance. Cold Spring Harb Perspect Biol. 4:a0069082012. View Article : Google Scholar

Chen X, Ghanizada M, Mallajosyula V, Sola E, Capasso R, Kathuria KR and Davis MM: Differential roles of human CD4+ and CD8+ regulatory T cells in controlling self-reactive immune responses. Nat Immunol. 26:230–239. 2025. View Article : Google Scholar

Coutinho A, Caramalho I, Seixas E and Demengeot J: Thymic commitment of regulatory T cells is a pathway of TCR-dependent selection that isolates repertoires undergoing positive or negative selection. Curr Top Microbiol Immunol. 293:43–71. 2005.

Kisielow P: How does the immune system learn to distinguish between good and evil? The first definitive studies of T cell central tolerance and positive selection. Immunogenetics. 71:513–518. 2019. View Article : Google Scholar

Spetz J, Presser AG and Sarosiek KA: T cells and regulated cell death: Kill or be killed. Int Rev Cell Mol Biol. 342:27–71. 2019. View Article : Google Scholar

Lv H, Havari E, Pinto S, Gottumukkala RVSRK, Cornivelli L, Raddassi K, Matsui T, Rosenzweig A, Bronson RT, Smith R, et al: Impaired thymic tolerance to α-Myosin directs autoimmunity to the heart in mice and humans. J Clin Invest. 121:1561–1573. 2011. View Article : Google Scholar

Sur M, Rasquinha MT, Arumugam R, Massilamany C, Gangaplara A, Mone K, Lasrado N, Yalaka B, Doiphode A, Gurumurthy C, et al: Transgenic mice expressing functional TCRs specific to cardiac Myhc-α 334–352 on Both CD4 and CD8 T cells are resistant to the development of myocarditis on C57BL/6 genetic background. Cells. 12:23462023. View Article : Google Scholar

Nindl V, Maier R, Ratering D, De Giuli R, Züst R, Thiel V, Scandella E, Di Padova F, Kopf M, Rudin M, et al: Cooperation of Th1 and Th17 cells determines transition from autoimmune myocarditis to dilated cardiomyopathy. Eur J Immunol. 42:2311–2321. 2012. View Article : Google Scholar

Raffin C, Vo LT and Bluestone JA: Treg Cell-based therapies: Challenges and perspectives. Nat Rev Immunol. 20:158–172. 2020. View Article : Google Scholar

Cheru N, Hafler DA and Sumida TS: Regulatory T cells in peripheral tissue tolerance and diseases. Front Immunol. 14:11545752023. View Article : Google Scholar

ElTanbouly MA and Noelle RJ: Rethinking peripheral T cell tolerance: Checkpoints across a T cell's journey. Nat Rev Immunol. 21:257–267. 2021. View Article : Google Scholar

Bluestone JA and Anderson M: Tolerance in the age of immunotherapy. N Engl J Med. 383:1156–1166. 2020. View Article : Google Scholar

Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 12:252–264. 2012. View Article : Google Scholar

Sharpe AH and Pauken KE: The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol. 18:153–167. 2018. View Article : Google Scholar

Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T and Sakaguchi S: CTLA-4 control over Foxp3+ regulatory T cell function. Science. 322:271–275. 2008. View Article : Google Scholar

Aggarwal V, Workman CJ and Vignali DAA: LAG-3 as the third checkpoint inhibitor. Nat Immunol. 24:1415–1422. 2023. View Article : Google Scholar

Grabie N, Lichtman AH and Padera R: T cell checkpoint regulators in the heart. Cardiovasc Res. 115:869–877. 2019. View Article : Google Scholar

Tan CL, Kuchroo JR, Sage PT, Liang D, Francisco LM, Buck J, Thaker YR, Zhang Q, McArdel SL, Juneja VR, et al: PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance. J Exp Med. 218:e201822322021. View Article : Google Scholar

Zhang A, Ren Z, Tseng K-F, Liu X, Li H, Lu C, Cai Y, Minna JD and Fu YX: Dual targeting of CTLA-4 and CD47 on Treg cells promotes immunity against solid tumors. Sci Transl Med. 13:eabg86932021. View Article : Google Scholar

Guo X, Wang H, Zhou J, Li Y, Duan L, Si X and Zhang L, Fang L and Zhang L: Clinical manifestation and management of immune checkpoint Inhibitor-associated cardiotoxicity. Thorac Cancer. 11:475–480. 2020. View Article : Google Scholar

Huertas RM, Serrano CS, Perna C, Gómez AF and Gordoa TA: Cardiac toxicity of Immune-checkpoint inhibitors: A clinical case of Nivolumab-induced myocarditis and review of the evidence and new challenges. Cancer Manag Res. 11:4541–4548. 2019. View Article : Google Scholar

Axelrod ML, Meijers WC, Screever EM, Qin J, Carroll MG, Sun X, Tannous E, Zhang Y, Sugiura A, Taylor BC, et al: T cells specific for α-Myosin drive Immunotherapy-related myocarditis. Nature. 611:818–826. 2022. View Article : Google Scholar

Lim SY, Lee JH, Gide TN, Menzies AM, Guminski A, Carlino MS, Breen EJ, Yang JYH, Ghazanfar S, Kefford RF, et al: Circulating cytokines predict Immune-related toxicity in melanoma patients receiving Anti-PD-1-based immunotherapy. Clin Cancer Res. 25:1557–1563. 2019. View Article : Google Scholar

Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, Hicks M, Puzanov I, Alexander MR, Bloomer TL, et al: Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 375:1749–1755. 2016. View Article : Google Scholar

Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, Zhao S, Das S, Beckermann KE, Ha L, et al: Fatal toxic effects associated with immune checkpoint inhibitors: A systematic review and Meta-analysis. JAMA Oncol. 4:1721–1728. 2018. View Article : Google Scholar

Martínez-Lostao L, Anel A and Pardo J: How do cytotoxic lymphocytes kill cancer cells? Clin Cancer Res. 21:5047–5056. 2015. View Article : Google Scholar

Del Re DP, Amgalan D, Linkermann A, Liu Q and Kitsis RN: Fundamental mechanisms of regulated cell death and implications for heart disease. Physiol Rev. 99:1765–1817. 2019. View Article : Google Scholar

Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, et al: Molecular mechanisms of cell death: Recommendations of the nomenclature committee on cell death 2018. Cell Death Differ. 25:486–541. 2018. View Article : Google Scholar

Voskoboinik I, Whisstock JC and Trapani JA: Perforin and Granzymes: Function, dysfunction and human pathology. Nat Rev Immunol. 15:388–400. 2015. View Article : Google Scholar

Wang W, Green M, Choi JE, Gijón M, Kennedy PD, Johnson JK, Liao P, Lang X, Kryczek I, Sell A, et al: CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 569:270–274. 2019. View Article : Google Scholar

Alshoubaki YK, Nayer B, Lu YZ, Salimova E, Lau SN, Tan JL, Amann-Zalcenstein D, Hickey PF, Del Monte-Nieto G, Vasanthakumar A, et al: Tregs Delivered Post-myocardial infarction adopt an Injury-specific phenotype promoting cardiac repair via macrophages in mice. Nat Commun. 15:64802024. View Article : Google Scholar

Zhu H, Galdos FX, Lee D, Waliany S, Huang YV, Ryan J, Dang K, Neal JW, Wakelee HA, Reddy SA, et al: Identification of pathogenic immune cell subsets associated with checkpoint Inhibitor-induced myocarditis. Circulation. 146:316–335. 2022. View Article : Google Scholar

Zhang N and Bevan MJ: CD8(+) T cells: Foot soldiers of the immune system. Immunity. 35:161–168. 2011. View Article : Google Scholar

Ma P, Liu J, Qin J, Lai L, Heo GS, Luehmann H, Sultan D, Bredemeyer A, Bajapa G, Feng G, et al: Expansion of pathogenic cardiac macrophages in immune checkpoint inhibitor myocarditis. Circulation. 149:48–66. 2024. View Article : Google Scholar

Blum SM, Zlotoff DA, Smith NP, Kernin IJ, Ramesh S, Zubiri L, Caplin J, Samanta N, Martin S, Wang M, et al: Immune responses in checkpoint myocarditis across heart, blood and tumour. Nature. 636:215–223. 2024. View Article : Google Scholar

Moslehi JJ, Brinkley DM and Meijers WC: Fulminant myocarditis: Evolving diagnosis, Evolving biology, evolving prognosis. J Am Coll Cardiol. 74:312–314. 2019. View Article : Google Scholar

Altan M, Toki MI, Gettinger SN, Carvajal-Hausdorf DE, Zugazagoitia J, Sinard JH, Herbst RS and Rimm DL: Immune checkpoint Inhibitor-associated pericarditis. J Thorac Oncol. 14:1102–1108. 2019. View Article : Google Scholar

Salem JE, Allenbach Y, Vozy A, Brechot N, Johnson DB, Moslehi JJ and Kerneis M: Abatacept for severe immune checkpoint Inhibitor-associated myocarditis. N Engl J Med. 380:2377–2379. 2019. View Article : Google Scholar

Grossman Z and Paul WE: Dynamic tuning of lymphocytes: Physiological basis, mechanisms, and function. Annu Rev Immunol. 33:677–713. 2015. View Article : Google Scholar

Schwartz DM, Bonelli M, Gadina M and O'Shea JJ: Type I/II Cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol. 12:25–36. 2016. View Article : Google Scholar

Yan L, Wang J, Cai X, Liou YC, Shen HM, Hao J, Huang C, Luo G and He W: Macrophage plasticity: Signaling pathways, tissue repair, and regeneration. MedComm. 5:e6582024. View Article : Google Scholar

Bracamonte-Baran W and Čiháková D: Cardiac autoimmunity: Myocarditis. Adv Exp Med Biol. 1003:187–221. 2017. View Article : Google Scholar

Cao Z, Zhang Y, Jia H, Sun X, Feng Y, Wu H, Xu B and Wei Z: Immune checkpoint inhibitors mediate myocarditis by promoting macrophage polarization via cGAS/STING pathway. Cytokine. 187:1568732025. View Article : Google Scholar

Chen G, Jiang H, Yao Y, Tao Z, Chen W, Huang F and Chen X: Macrophage, a potential targeted therapeutic immune cell for cardiomyopathy. Front Cell Dev Biol. 10:9087902022. View Article : Google Scholar

Munir AZ, Gutierrez A, Qin J, Lichtman AH and Moslehi JJ: Immune-checkpoint inhibitor-mediated myocarditis: CTLA4, PD1 and LAG3 in the heart. Nat Rev Cancer. 24:540–553. 2024. View Article : Google Scholar

Thibult ML, Mamessier E, Gertner-Dardenne J, Pastor S, Just-Landi S, Xerri L, Chetaille B and Olive D: PD-1 is a novel regulator of Human B-cell activation. Int Immunol. 25:129–137. 2013. View Article : Google Scholar

Lu J, Wu J, Mao L, Xu H and Wang S: Revisiting PD-1/PD-L pathway in T and B cell response: Beyond immunosuppression. Cytokine Growth Factor Rev. 67:58–65. 2022. View Article : Google Scholar

Esen F, Deniz G and Aktas EC: PD-1, CTLA-4, LAG-3, and TIGIT: The roles of immune checkpoint receptors on the regulation of human NK cell phenotype and functions. Immunol Lett. 240:15–23. 2021. View Article : Google Scholar

Judge SJ, Dunai C, Aguilar EG, Vick SC, Sturgill IR, Khuat LT, Stoffel KM, Van Dyke J, Longo DL, Darrow MA, et al: Minimal PD-1 expression in mouse and human NK cells under diverse conditions. J Clin Invest. 130:3051–3068. 2020. View Article : Google Scholar

Merino A, Zhang B, Dougherty P, Luo X, Wang J, Blazar BR, Miller JS and Cichocki F: Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming. J Clin Invest. 129:3770–3785. 2019. View Article : Google Scholar

Racine JJ, Bachman JF, Zhang JG, Misherghi A, Khadour R, Kaisar S, Bedard O, Jenkins C, Abbott A, Forte E, et al: Murine MHC-deficient nonobese diabetic mice carrying human HLA-DQ8 develop severe myocarditis and myositis in response to anti-PD-1 immune checkpoint inhibitor cancer therapy. J Immunol. 212:1287–1306. 2024. View Article : Google Scholar

Taneja V and David CS: Spontaneous autoimmune myocarditis and cardiomyopathy in HLA-DQ8.NODAbo transgenic mice. J Autoimmun. 33:260–269. 2009. View Article : Google Scholar

Taylor JA, Havari E, McInerney MF, Bronson R, Wucherpfennig KW and Lipes MA: A spontaneous model for autoimmune myocarditis using the human MHC molecule HLA-DQ8. J Immunol. 172:2651–2658. 2004. View Article : Google Scholar

Konstantina T, Konstantinos R, Anastasios K, Anastasia M, Eleni L, Ioannis S, Sofia A and Dimitris M: Fatal adverse events in two thymoma patients treated with anti-PD-1 immune check point inhibitor and literature review. Lung Cancer. 135:29–32. 2019. View Article : Google Scholar

Chen Q, Huang DS, Zhang LW, Li YQ, Wang HW and Liu HB: Fatal myocarditis and rhabdomyolysis induced by nivolumab during the treatment of type B3 thymoma. Clin Toxicol (Phila). 56:667–671. 2018. View Article : Google Scholar

Nguyen LS, Bretagne M, Arrondeau J, Zahr N, Ederhy S, Abbar B, Pinna B, Allenbach Y, Mira JP, Moslehi J, et al: Reversal of Immune-checkpoint inhibitor fulminant myocarditis using Personalized-Dose-Adjusted abatacept and ruxolitinib: Proof of concept. J Immunother Cancer. 10:e0046992022. View Article : Google Scholar

Huang GZ and Lo YL: Correlation between acetylcholine receptor antibody levels and thymic pathology in myasthenia gravis: A review. J Clin Neuromuscul Dis. 14:209–217. 2013. View Article : Google Scholar

Régnier P, Le Joncour A, Maciejewski-Duval A, Darrasse-Jèze G, Dolladille C, Meijers WC, Bastarache L, Fouret P, Bruneval P, Arbaretaz F, et al: CTLA-4 pathway is instrumental in giant cell arteritis. Circ Res. 133:298–312. 2023. View Article : Google Scholar

Gil-Cruz C, Perez-Shibayama C, De Martin A, Ronchi F, van der Borght K, Niederer R, Onder L, Lütge M, Novkovic M, Nindl V, et al: Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy. Science. 366:881–886. 2019. View Article : Google Scholar

Muser D, Santangeli P and Liang JJ: Mechanisms of ventricular arrhythmias and implications for catheter ablation. Card Electrophysiol Clin. 14:547–558. 2022. View Article : Google Scholar

Francis Stuart SD, De Jesus NM, Lindsey ML and Ripplinger CM: The crossroads of inflammation, fibrosis, and arrhythmia following myocardial infarction. J Mol Cell Cardiol. 91:114–122. 2016. View Article : Google Scholar

Hulsmans M, Clauss S, Xiao L, Aguirre AD, King KR, Hanley A, Hucker WJ, Wulfers EM, Seemann G, Courties G, et al: Macrophages facilitate electrical conduction in the heart. Cell. 169:510–522.e20. 2017. View Article : Google Scholar

Zhang Y, Qin J, Amancherla K, Jing Y, Hu Q, Liang K, Zhang Z, Ye Y, Huang LA, Nguyen TK, et al: Hormonal therapies upregulate MANF and overcome female susceptibility to immune checkpoint inhibitor-myocarditis. Sci Transl Med. 14:eabo19812022. View Article : Google Scholar

Feng S, Yang M, Dong P, Ding F, Hong Y, Cai H and Liu X: Investigation of MANF regulation of glioma stemness via STAT3/TGF-β/SMAD4/p38 pathway based on pan-cancer analysis. Transl Oncol. 60:1024972025. View Article : Google Scholar

Zhang Y, Sun C, Li Y, Qin J, Amancherla K, Jing Y, Hu Q, Liang K, Zhang Z, Ye Y, et al: Hormonal therapies Up-Regulate MANF and overcome female susceptibility to immune checkpoint inhibitor myocarditis. Sci Transl Med. 14:eabo19812022. View Article : Google Scholar

Wang J and Han B: Dysregulated CD4+ T cells and microRNAs in myocarditis. Front Immunol. 11:5392020. View Article : Google Scholar

Tajczak PM and Jóźwik K: Artificial intelligence and myocarditis-a systematic review of current applications. Heart Fail Rev. 29:1217–1234. 2024. View Article : Google Scholar

Brahmer JR, Abu-Sbeih H, Ascierto PA, Brufsky J, Cappelli LC, Cortazar FB, Gerber DE, Hamad L, Hansen E, Johnson DB, et al: Society for Immunotherapy of cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer. 9:e0024352021. View Article : Google Scholar

Quan Z, Yang Y, Zheng H, Zhan Y, Luo J, Ning Y and Fan S: Clinical Implications of the interaction between PD-1/PD-L1 and PI3K/AKT/mTOR pathway in progression and treatment of non-small cell lung cancer. J Cancer. 13:3434–3443. 2022. View Article : Google Scholar

Ramayya T, Mitchell JD, Hartupee JC, Lavine K, Ridley CH, Kotkar KD, Jimenez J, Lin CY, Alvarez-Cardona JA, Krone RK and Campbell CM: Delayed diagnosis and recovery of fulminant immune checkpoint Inhibitor-associated myocarditis on VA-ECMO support. JACC CardioOncol. 4:722–726. 2022. View Article : Google Scholar

Osinga TE, Oosting SF, van der Meer P, de Boer RA, Kuenen BC, Rutgers A, Bergmann L, Oude Munnink TH, Jalving M and van Kruchten M: Immune checkpoint inhibitor-associated myocarditis: Case reports and a review of the literature. Neth Heart J. 30:295–301. 2022. View Article : Google Scholar

Lipe DN, Qdaisat A, Krishnamani PP, Nguyen TD, Chaftari P, El Messiri N, Srinivasan A, Galvis-Carvajal E and Reyes-Gibby CC: Myocarditis, myositis, and myasthenia gravis overlap syndrome associated with immune checkpoint inhibitors: A systematic review. Diagnostics (Basel). 14:17942024. View Article : Google Scholar

Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins S, Anadkat M, Atkins MB, Brassil KJ, Caterino JM, Chau I, et al: Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. 39:4073–4126. 2021. View Article : Google Scholar

Lyon AR, Lopez-Fernandez T, Couch LS, Asteggiano R, Aznar MC, Bergler-Klein J, Boriani G, Cardinale D, Cordoba R, Cosyns B, et al: 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 43:4229–4361. 2022. View Article : Google Scholar