Digestive System Toxicities of Immune Checkpoint Inhibitors: Mechanisms and Clinical Implications

Abstract

Immune checkpoint inhibitors (ICIs) have achieved remarkable efficacy in treating malignancies but may simultaneously induce immune-related adverse events (irAEs), among which ICI-related digestive system adverse events (ir-DSAEs) occur with relatively high frequency and present severe clinical manifestations. This review systematically examined ir-DSAEs, including clinical presentations, pathogenic mechanisms, risk factors, diagnostic approaches, and therapeutic strategies. It has been reported that ir-DSAEs primarily include colitis, hepatitis, and pancreatitis with underlying mechanisms involving T cell-mediated inflammatory responses, cytokine storm, activation of autoimmune reactions, and alterations in gut microbiota. The diagnosis of ir-DSAEs requires integration of multiple approaches. Standardized therapeutic strategies include treatment regimen adjustments, corticosteroid administration, use of selective immunosuppressants, and comprehensive supportive care. An in-depth understanding of ir-DSAEs has significant clinical implications for enhancing the safety and efficacy of ICI therapy, thereby providing a theoretical foundation for future precise prediction, prevention, and treatment of ir-DSAEs.

Keywords

Biological mechanisms / cancer / digestive system adverse events / immune checkpoint inhibitors

References

[1] Lin A, Ye P, Li Z, Jiang A, Liu Z, et al. Natural killer cell immune checkpoints and their therapeutic targeting in cancer treatment. Research (Wash D C) 2025; 8: 0723. [PMID: 40463500 DOI: 10.34133/resaerch.0723]

[2] Kostecki KL, Iida M, Crossman BE, Salgia R, Harari PM, et al. Immune escape strategies in head and neck cancer: evade, resist, inhibit, recruit. Cancers 2024; 16(2): 312. [PMID: 38254801 DOI: 10.3390/cancers16020312]

[3] Dermani FK, Samadi P, Rahmani G, Kohlan AK, Najafi R. PD-1/PD-L1 immune checkpoint: potential target for cancer therapy. J Cell Physiol 2019; 234(2): 1313-25. [PMID: 30191996 DOI: 10.1002/jcp.27172]

[4] Sangro B, Chan SL, Meyer T, Reig M, El-Khoueiry A, et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J Hepatol 2020; 72(2): 320-41. [PMID: 31954495 DOI: 10.1016/j.jhep.2019.10.021]

[5] Zeng M, Lin A, Jiang A, Qiu Z, Zhang H, et al. Decoding the mechanisms behind second primary cancers. J Transl Med 2025; 23(1): 115. [PMID: 39856672 DOI: 10.1186/s12967-025-06151-9]

[6] Cheng AL, Hsu C, Chan SL, Choo SP, Kudo M. Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma. J Hepatol 2020; 72(2): 307-19. [PMID: 31954494 DOI: 10.1016/j.jhep.2019.09.025]

[7] Li Y, Kang X, Wang H, Guo X, Zhou J, et al. Clinical diagnosis and treatment of immune checkpoint inhibitor-associated adverse events in the digestive system. Thorac Cancer 2020; 11(4): 829-34. [PMID: 32107847 DOI: 10.1111/1759-7714.13338]

[8] Liu L, Xie Y, Yang H, Lin A, Dong M, et al. HPVTIMER: a shiny web application for tumor immune estimation in human papillomavirus-associated cancers. iMeta 2023; 2(3): e130. [PMID: 38867938 DOI: 10.1002/imt2.130]

[9] Shi X, Cheng X, Jiang A, Shi W, Zhu L, et al. Immune checkpoints in B cells: unlocking new potentials in cancer treatment. Adv Sci (Weinh) 2024; 11(47): e2403423. [PMID: 39509319 DOI: 10.1002/advs.202403423]

[10] Aggarwal V, Workman CJ, Vignali DAA. LAG-3 as the third checkpoint inhibitor. Nat Immunol 2023; 24(9): 1415-22. [PMID: 37488429 DOI: 10.1038/s41590-023-01569-z]

[11] Lin A, Qi C, Wei T, Li M, Cheng Q, et al. CAMOIP: a web server for comprehensive analysis on multi-omics of immunotherapy in pan-cancer. Brief Bioinform 2022; 23(3): bbac129. [PMID: 35395670 DOI: 10.1093/bib/bbac129]

[12] Gu T, Jiang A, Zhou C, Lin A, Cheng Q, et al. Adverse reactions associated with immune checkpoint inhibitors and bevacizumab: a pharmacovigilance analysis. Int J Cancer 2023; 152(3): 480-95. [PMID: 36274626 DOI: 10.1002/ijc.34332]

[13] Zhou C, Peng S, Lin A, Jiang A, Peng Y, Gu T, et al. Psychiatric disorders associated with immune checkpoint inhibitors: a pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database. EClinicalMedicine 2023; 59: 101967. [PMID: 37131541 DOI: 10.1016/j.eclinm.2023.101967]

[14] Lin A, Zheng K, Jiang A, Huang X, Wang Q, et al. The evolving landscape of immunotoxicity: charting mechanisms and future strategies for immune checkpoint inhibitor adverse events. Med Res 2025; 1(3): 322-58. [DOI: 10.1002/mdr2.70019]

[15] Frey C, Etminan M. Adverse events of PD-1, PD-L1, CTLA-4, and LAG-3 immune checkpoint inhibitors: an analysis of the FDA adverse events database. Antibodies (Basel) Switz 2024; 13(3): 59. [PMID: 39051335 DOI: 10.3390/antib13030059]

[16] Regev A, Avigan MI, Kiazand A, Vierling JM, Lewis JH, et al. Best practices for detection, assessment and management of suspected immune-mediated liver injury caused by immune checkpoint inhibitors during drug development. J Autoimmun 2020; 114: 102514. [PMID: 32768244 DOI: 10.1016/j.jaut.2020.102514]

[17] Kataoka S, Moriguchi M, Okishio S, Takahashi A, Okuda K, et al. Re-administration of nivolumab after immune checkpoint inhibitor-induced cholangitis: the first reported case. Clin J Gastroenterol 2022; 15(2): 467-74. [PMID: 35201598 DOI: 10.1007/s12328-022-01590-z]

[18] Autio KA, Boni V, Humphrey RW, Naing A. Probody therapeutics: an emerging class of therapies designed to enhance on-target effects with reduced off-tumor toxicity for use in immuno-oncology. Clin Cancer Res 2020; 26(5): 984-9. [PMID: 31601568 DOI: 10.1158/1078-0432.CCR-19-1457]

[19] Bhardwaj M, Chiu MN, Pilkhwal Sah S. Adverse cutaneous toxicities by PD-1/PD-L1 immune checkpoint inhibitors: pathogenesis, treatment, and surveillance. Cutan Ocul Toxicol 2022; 41(1): 73-90. [PMID: 35107396 DOI: 10.1080/15569527.2022.2034842]

[20] Wang Y, Zhou S, Yang F, Qi X, Wang X, et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis. JAMA Oncol 2019; 5(7): 1008-19.

[21] Riveiro-Barciela M, Carballal S, Díaz-González Á, Mañosa M, Gallego-Plazas J, et al. Management of liver and gastrointestinal toxicity induced by immune checkpoint inhibitors: position statement of the AEEH-AEG-SEPD-SEOM-GETECCU. Gastroenterol Hepatol 2024; 47(4): 401-32. [PMID: 38228461 DOI: 10.1016/j.gastrohep.2023.10.009]

[22] Tan B, Li Y, Xu Y, Chen M, Wang M, et al. Recognition and management of the gastrointestinal and hepatic immune-related adverse events. Asia Pac J Clin Oncol 2020; 16(3): 95-102. [PMID: 32077625 DOI: 10.1111/ajco.13317]

[23] Miao K, Zhang L. Incidence rate and treatment strategy of immune checkpoint inhibitor mediated hepatotoxicity: a systematic review. Cancer Pathog Ther 2023; 1(1): 46-55. [PMID: 38328612 DOI: 10.1016/j.cpt.2022.11.003]

[24] Lin A, Jiang A, Huang L, Li Y, Zhang C, et al. From chaos to order: optimizing fecal microbiota transplantation for enhanced immune checkpoint inhibitors efficacy. Gut Microbes 2025; 17(1): 2452277. [PMID: 39826104 DOI: 10.1080/19490976.2025.2452277]

[25] Chennamadhavuni A, Abushahin L, Jin N, Presley CJ, Manne A. Risk factors and biomarkers for immune-related adverse events: a practical guide to identifying high-risk patients and rechallenging immune checkpoint inhibitors. Front Immunol 2022; 13: 779691. [PMID: 35558065 DOI: 10.3389/fimmu.2022.779691]

[26] Auch LAM, Sieber C, Lehnick D, Hug BL. Adverse drug events of immune checkpoint inhibitors - a retrospective, descriptive real-world data analysis. BMC Cancer 2025; 25(1): 1303. [PMID: 40790180 DOI: 10.1186/s12885-025-14733-5]

[27] Nielsen DL, Juhl CB, Chen IM, Kellermann L, Nielsen OH. Immune checkpoint inhibitor-induced diarrhea and colitis: incidence and management. A systematic review and meta-analysis. Cancer Treat Rev 2022; 109: 102440. [PMID: 35917654 DOI: 10.1016/j.ctrv.2022.102440]

[28] Gupta A, De Felice KM, Loftus EV Jr, Khanna S. Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment Pharmacol Ther 2015; 42(4): 406-17. [PMID: 26079306 DOI: 10.1111/apt.13281]

[29] Tian Y, Abu-Sbeih H, Wang Y. Immune checkpoint inhibitors-induced colitis. Adv Exp Med Biol 2018; 995: 151-7. [PMID: 30539510 DOI: 10.1007/978-3-030-02505-2_7]

[30] Tang L, Wang J, Lin N, Zhou Y, He W, et al. Immune checkpoint inhibitor-associated colitis: from mechanism to management. Front Immunol 2021; 12: 800879. [PMID: 34992611 DOI: 10.3389/fimmu.2021.800879]

[31] Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012; 30(21): 2691-7. [PMID: 22614989 DOI: 10.1200/JCO.2012.41.6750]

[32] Wang DY, Ye F, Zhao S, Johnson DB. Incidence of immune checkpoint inhibitor-related colitis in solid tumor patients: a systematic review and meta-analysis. Oncoimmunology 2017; 6(10): e1344805. [PMID: 29123955 DOI: 10.1080/2162402X.2017.1344805]

[33] Zoghbi M, Burk KJ, Haroun E, Saade M, Carreras MTC. Immune checkpoint inhibitor-induced diarrhea and colitis: an overview. Support Care Cancer 2024; 32(10): 680. [PMID: 39311981 DOI: 10.1007/s00520-024-08889-2]

[34] Yoshino K, Nakayama T, Ito A, Sato E, Kitano S. Severe colitis after PD-1 blockade with nivolumab in advanced melanoma patients: potential role of Th1-dominant immune response in immune-related adverse events: two case reports. BMC Cancer 2019; 19(1): 1019. [PMID: 31664934 DOI: 10.1186/s12885-019-6138-7]

[35] Ni CX, Zhao Y, Qian H, Fu H, Yan YY, et al. Long survival in a pancreatic carcinoma patient with multi-organ toxicities after sintilimab treatment: a case report. Front Pharmacol 2023; 14: 1121122. [PMID: 36744247 DOI: 10.3389/fphar.2023.1121122]

[36] Dougan M. Checkpoint blockade toxicity and immune homeostasis in the gastrointestinal tract. Front Immunol 2017; 8: 1547. [PMID: 29230210 DOI: 10.3389/fimmu.2017.01547]

[37] Soularue E, Lepage P, Colombel JF, Coutzac C, Faleck D, et al. Enterocolitis due to immune checkpoint inhibitors: a systematic review. Gut 2018; 67(11): 2056-67. [PMID: 30131322 DOI: 10.1136/gutjnl-2018-316948]

[38] Som A, Mandaliya R, Alsaadi D, Farshidpour M, Charabaty A, et al. Immune checkpoint inhibitor-induced colitis: a comprehensive review. World J Clin Cases 2019; 7(4): 405-18. [PMID: 30842952 DOI: 10.12998/wjcc.v7.i4.405]

[39] Benson AB 3rd, Ajani JA, Catalano RB, Engelking C, Kornblau SM, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol 2004; 22(14): 2918-26. [PMID: 15254061 DOI: 10.1200/JCO.2004.04.132]

[40] Kubo T, Hirohashi Y, Keira Y, Akimoto M, Ikeda T, et al. Identification of characteristic subepithelial surface granulomatosis in immune-related adverse event-associated enterocolitis. Cancer Sci 2021; 112(3): 1320-5. [PMID: 33459466 DOI: 10.1111/cas.14773]

[41] Dougan M, Blidner AG, Choi J, Cooksley T, Glezerman I, et al. Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of severe gastrointestinal and hepatic toxicities from checkpoint inhibitors. Support Care Cancer 2020; 28(12): 6129-43. [PMID: 32856210 DOI: 10.1007/s00520-020-05707-3]

[42] Jiang Y, Li R, Li X, Zhang N. Risk factors of immune-mediated hepatotoxicity induced by immune checkpoint inhibitors in cancer patients: a systematic review and meta-analysis. Curr Oncol 2024; 31(11): 7129-43. [PMID: 39590156 DOI: 10.3390/curroncol31110525]

[43] Parlati L, Vallet-Pichard A, Batista R, Hernvann A, Sogni P, et al. Incidence of grade 3-4 liver injury under immune checkpoints inhibitors: a retrospective study. J Hepatol 2018; 69(6): 1396-7. [PMID: 30292476 DOI: 10.1016/j.jhep.2018.08.014]

[44] Imoto K, Kohjima M, Hioki T, Kurashige T, Kurokawa M, et al. Clinical features of liver injury induced by immune checkpoint inhibitors in Japanese patients. Can J Gastroenterol Hepatol 2019; 2019: 6391712. [PMID: 31929981 DOI: 10.1155/2019/6391712]

[45] Remash D, Prince DS, McKenzie C, Strasser SI, Kao S, et al. Immune checkpoint inhibitor-related hepatotoxicity: a review. World J Gastroenterol 2021; 27(32): 5376-91. [PMID: 34539139 DOI: 10.3748/wjg.v27.i32.5376]

[46] Cui TM, Liu Y, Wang JB, Liu LX. Adverse effects of immune-checkpoint inhibitors in hepatocellular carcinoma. OncoTargets Ther 2020; 13: 11725-40. [PMID: 33235462 DOI: 10.2147/OTT.S279858]

[47] Coukos A, Vionnet J, Obeid M, Bouchaab H, Peters S, et al. Systematic comparison with autoimmune liver disease identifies specific histological features of immune checkpoint inhibitor-related adverse events. J Immunother Cancer 2022; 10(10): e005635. [PMID: 36283734 DOI: 10.1136/jitc-2022-005635]

[48] Kawakami H, Tanizaki J, Tanaka K, Haratani K, Hayashi H, et al. Imaging and clinicopathological features of nivolumab-related cholangitis in patients with non-small cell lung cancer. Invest New Drugs 2017; 35(4): 529-36. [PMID: 28317087 DOI: 10.1007/s10637-017-0453-0]

[49] Onoyama T, Takeda Y, Yamashita T, Hamamoto W, Sakamoto Y, et al. Programmed cell death-1 inhibitor-related sclerosing cholangitis: a systematic review. World J Gastroenterol 2020; 26(3): 353-65. [PMID: 31988594 DOI: 10.3748/wjg.v26.i3.353]

[50] Nakano R, Shiomi H, Fujiwara A, Yoshihara K, Yoshioka R, et al. Clinical characteristics of ICI-related pancreatitis and cholangitis including radiographic and endoscopic findings. Healthcare (Basel) 2022; 10(5): 763. [PMID: 35627900 DOI: 10.3390/healthcare10050763]

[51] Tanaka T, Sakai A, Shiomi H, Masuda A, Kobayashi T, et al. An autopsy case of severe acute pancreatitis induced by administration of pazopanib following nivolumab. Pancreatology 2021; 21(1): 21-4. [PMID: 33184007 DOI: 10.1016/j.pan.2020.11.002]

[52] Ichiki T, Hori Y, Tsuji Y. Two types of immune checkpoint inhibitor-related pancreatitis. Intern Med Tokyo Jpn 2022; 61(10): 1477-8. [PMID: 34744111 DOI: 10.2169/internalmedicine.8452-21]

[53] Yazaki T, Moriyama I, Tobita H, Sonoyama H, Okimoto E, et al. The simultaneous onset of pancreatitis and colitis as immune-related adverse events in a patient receiving nivolumab treatment for renal cell carcinoma. Intern Med 2022; 61(10): 1485-90. [PMID: 34744104 DOI: 10.2169/internalmedicine.7911-21]

[54] Ueno M, Tsuji Y, Yokoyama T, Koyama T, Uenishi Y, et al. Fatal immune checkpoint inhibitor-related pancreatitis. Intern Med 2021; 60(24): 3905-11. [PMID: 34121010 DOI: 10.2169/internalmedicine.7366-21]

[55] Di Giacomo AM, Danielli R, Guidoboni M, Calabrò L, Carlucci D, et al. Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases. Cancer Immunol Immunother 2009; 58(8): 1297-306. [PMID: 19139884 DOI: 10.1007/s00262-008-0642-y]

[56] Abu-Sbeih H, Tang T, Lu Y, Thirumurthi S, Altan M, et al. Clinical characteristics and outcomes of immune checkpoint inhibitor-induced pancreatic injury. J Immunother Cancer 2019; 7(1): 31. [PMID: 30728076 DOI: 10.1186/s40425-019-0502-7]

[57] Xu Y, Wen N, Sonis ST, Villa A. Oral side effects of immune checkpoint inhibitor therapy (ICIT): an analysis of 4683 patients receiving ICIT for malignancies at Massachusetts General Hospital, Brigham & Women’s Hospital, and the Dana-Farber Cancer Institute, 2011 to 2019. Cancer 2021; 127(11): 1796-804. [PMID: 33595843 DOI: 10.1002/cncr.33436]

[58] Asan MF, Castelino RL, Babu SG, Rao K, Pandita V. Oral immune-related adverse events - current concepts and their management. Asia Pac J Oncol Nurs 2021; 8(6): 604-9. [PMID: 34790844 DOI: 10.4103/apjon.apjon-2136]

[59] Raber-Durlacher JE, Elad S, Barasch A. Oral mucositis. Oral Oncol 2010; 46(6): 452- 6. [PMID: 20403721 DOI: 10.1016/j.oraloncology.2010.03.012]

[60] Xu T, Liu Y, Lu X, Liang J. Toxicity profile of combined immune checkpoint inhibitors and thoracic radiotherapy in esophageal cancer: a meta-analysis and systematic review. Front Immunol 2022; 13: 1039020. [PMID: 36439117 DOI: 10.3389/fimmu.2022.1039020]

[61] Shatila M, Zhang HC, Shirwaikar Thomas A, Machado AP, Naz S, et al. Systematic review of immune checkpoint inhibitor-related gastrointestinal, hepatobiliary, and pancreatic adverse events. J Immunother Cancer 2024; 12(11): e009742. [PMID: 39542654 DOI: 10.1136/jitc-2024-009742]

[62] Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192(7): 1027-34. [PMID: 39542654 DOI: 10.1136/jitc-2024-009742]

[63] Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, et al. A new member of the immunoglobulin superfamily——CTLA-4. Nature 1987; 328(6127): 267-70. [PMID: 3496540 DOI: 10.1038/328267a0]

[64] Robert L, Tsoi J, Wang X, Emerson R, Homet B, et al. CTLA4 blockade broadens the peripheral T-cell receptor repertoire. Clin Cancer Res 2014; 20(9): 2424-32. [PMID: 24583799 DOI: 10.1158/1078-0432.CCR-13-2648]

[65] Sullivan RJ, Weber JS. Immune-related toxicities of checkpoint inhibitors: mechanisms and mitigation strategies. Nat Rev Drug Discov 2022; 21(7): 495-508. [PMID: 34316029 DOI: 10.1038/s41573-021-00259-5]

[66] Li Y, Zhang C, Jiang A, Lin A, Liu Z, et al. Potential anti-tumor effects of regulatory T cells in the tumor microenvironment: a review. J Transl Med 2024; 22(1): 293. [PMID: 38509593 DOI: 10.1186/s12967-024-05104-y]

[67] Wing JB, Tanaka A, Sakaguchi S. Human FOXP3⁺ regulatory T cell heterogeneity and function in autoimmunity and cancer. Immunity 2019; 50(2): 302-16. [PMID: 30784578 DOI: 10.1016/j.immuni.2019.01.020]

[68] Gupta T, Antanaviciute A, Hyun-Jung Lee C, Ottakandathil Babu R, Aulicino A, et al. Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis. Cancer Cell 2024; 42(5): 797-814.e15. [PMID: 38744246 DOI: 10.1016/j.ccell.2024.04.010]

[69] Peng S, Lin A, Jiang A, Zhang C, Zhang J, et al. CTLs heterogeneity and plasticity: implications for cancer immunotherapy. Mol Cancer 2024; 23(1): 58. [PMID: 38515134 DOI: 10.1186/s12943-024-01972-6]

[70] Luoma AM, Suo S, Williams HL, Sharova T, Sullivan K, et al. Molecular pathways of colon inflammation induced by cancer immunotherapy. Cell 2020; 182(3): 655-71.e22. [PMID: 32603654 DOI: 10.1016/j.cell.2020.06.001]

[71] Bamias G, Delladetsima I, Perdiki M, Siakavellas SI, Goukos D, et al. Immunological characteristics of colitis associated with anti-CTLA-4 antibody therapy. Cancer Invest 2017; 35(7): 443-55. [PMID: 28548891 DOI: 10.1080/07357907.2017.1324032]

[72] Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014; 124(2): 188-95. [PMID: 24876563 DOI: 10.1182/blood-2014-05-552729]

[73] Jarczak D, Nierhaus A. Cytokine storm-definition, causes, and implications. Int J Mol Sci 2022; 23(19): 11740. [PMID: 36233040 DOI: 10.3390/ijms231911740]

[74] Ceschi A, Noseda R, Palin K, Verhamme K. Immune checkpoint inhibitor-related cytokine release syndrome: analysis of WHO global pharmacovigilance database. Front Pharmacol 2020; 11: 557. [PMID: 32425791 DOI: 10.3389/fphar.2020.00557]

[75] He D, Xu Y, Liu M, Cui L. The inflammatory puzzle: piecing together the links between neuroinflammation and amyotrophic lateral sclerosis. Aging Dis 2024; 15(1): 96-114. [PMID: 37307819 DOI: 10.14336/AD.2023.0519]

[76] Jones BE, Maerz MD, Buckner JH. IL-6: a cytokine at the crossroads of autoimmunity. Curr Opin Immunol 2018; 55: 9-14. [PMID: 30248523 DOI: 10.1016/j.coi.2018.09.002]

[77] Meng Y, Lv Y, Shen M, Yu W, Liu Y, et al. Establishment of an animal model of immune-related adverse events induced by immune checkpoint inhibitors. Cancer Med 2024; 13(14): e70011. [PMID: 39001676 DOI: 10.1002/cam4.70011]

[78] Endo Y, Winarski KL, Sajib MS, Ju A, Wu WJ. Atezolizumab induces necroptosis and contributes to hepatotoxicity of human hepatocytes. Int J Mol Sci 2023; 24(14): 11694. [PMID: 37511454 DOI: 10.3390/ijms241411694]

[79] Yang H, Yao Z, Zhou X, Zhang W, Zhang X, et al. Immune-related adverse events of checkpoint inhibitors: insights into immunological dysregulation. Clin Immunol 2020; 213: 108377. [PMID: 32135278 DOI: 10.1016/j.clim.2020.108377]

[80] Reynoso ED, Elpek KG, Francisco L, Bronson R, Bellemare-Pelletier A, et al. Intestinal tolerance is converted to autoimmune enteritis upon PD-1 ligand blockade. J Immunol 2009; 182(4): 2102-12. [PMID: 19201863 DOI: 10.4049/jimmunol.0802769]

[81] Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 2016; 54: 139-48. [PMID: 26765102 DOI: 10.1016/j.ejca.2015.11.016]

[82] Lin A, Xiong M, Jiang A, Huang L, Wong HZH, et al. The microbiome in cancer. iMeta 2025; 4(5): e70070. [PMID: 41112042 DOI: 10.1002/imt2.70070]

[83] Li D, Wu R, Yu Q, Tuo Z, Wang J, et al. Microbiota and urinary tumor immunity: mechanisms, therapeutic implications, and future perspectives. Chin J Cancer Res 2024; 36(6): 596-615. [PMID: 39802902 DOI: 10.21147/j.issn.1000-9604.2024.06.03]

[84] Zhang M, Xie F, Zhou F. The impact of intestinal microbiota-derived metabolites on cancer and their potential application in tumor immunotherapy. MedComm - Futur Med 2024; 3(3): e92. [DOI: 10.1002/mef2.92]

[85] Zhao B, Zhou B, Li Q, Su C, Ma J, et al. Harnessing the gut microbiome to enhance cancer immunotherapy: current advances and future directions in microbiota-based therapeutic strategies. MedComm - Futur Med 2024; 3(4): e70006. [DOI: 10.1002/mef2.70006]

[86] Huang L, Li Y, Zhang C, Jiang A, Zhu L, et al. Microbiome meets immunotherapy: unlocking the hidden predictors of immune checkpoint inhibitors. NPJ Biofilms Microbiomes 2025; 11(1): 180. [PMID: 40897718 DOI: 10.1038/s41522-025-00819-2]

[87] Lin A, Huang L, Jiang A, Zhu L, Mou W, et al. Microbiota boost immunotherapy? A meta-analysis dives into fecal microbiota transplantation and immune checkpoint inhibitors. BMC Med 2025; 23(1): 341. [DOI: 10.1186/s12916-025-04183-y]

[88] Situ Y, Zhang P, Zhang C, Jiang A, Zhang N, et al. The metabolic dialogue between intratumoural microbes and cancer: implications for immunotherapy. EBioMedicine 2025; 115: 105708. [PMID: 40267755 DOI: 10.1016/j.ebiom.2025.105708]

[89] Wang Y, Wiesnoski DH, Helmink BA, Gopalakrishnan V, Choi K, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med 2018; 24(12): 1804-8. [PMID: 30420754 DOI: 10.1038/s41591-018-0238-9]

[90] Wang T, Zheng N, Luo Q, Jiang L, He B, et al. Probiotics Lactobacillus reuteri abrogates immune checkpoint blockade-associated colitis by inhibiting group 3 innate lymphoid cells. Front Immunol 2019; 10: 1235. [PMID: 31214189 DOI: 10.3389/fimmu.2019.01235]

[91] Sun S, Luo L, Liang W, Yin Q, Guo J, et al. Bifidobacterium alters the gut microbiota and modulates the functional metabolism of T regulatory cells in the context of immune checkpoint blockade. Proc Natl Acad Sci U S A 2020; 117(44): 27509-15. [PMID: 33077598 DOI: 10.1073/pnas.1921223117]

[92] Knox NC, Forbes JD, Peterson CL, Van Domselaar G, Bernstein CN. The gut microbiome in inflammatory bowel disease: lessons learned from other immune-mediated inflammatory diseases. Am J Gastroenterol 2019; 114(7): 1051-70. [PMID: 31232832 DOI: 10.14309/ajg.0000000000000305]

[93] Zheng C, Huang S, Lin M, Hong B, Ni R, et al. Hepatotoxicity of immune checkpoint inhibitors: what is currently known. Hepatol Commun 2023; 7(3): e0063. [PMID: 36802366 DOI: 10.1097/HC9.0000000000000063]

[94] Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins S, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO Guideline Update. J Clin Oncol 2021; 39(36): 4073-126. [PMID: 34724392 DOI: 10.1200/JCO.21.01440]

[95] Yamamoto N, Nakanishi Y, Gemma A, Nakagawa K, Sakamoto T, et al. Real-world safety of nivolumab in patients with non-small-cell lung cancer in Japan: postmarketing surveillance. Cancer Sci 2021; 112(11): 4692-701. [PMID: 34431585 DOI: 10.1111/cas.15117]

[96] Hao Y, Lin G, Xiang J, Wang W, Xu C, et al. Analysis of the efficacy and safety of immunotherapy in advanced thymoma patients. Cancer Med 2023; 12(5): 5649-55. [PMID: 36394097 DOI: 10.1002/cam4.5357]

[97] Ge X, Jiang W, Li H, Wu Y, Li X, et al. Immune-related adverse events and outcomes among pan-cancer patients receiving immune checkpoint inhibitors: a monocentric real-world observational study. Cancer Med 2023; 12(18): 18491-502. [PMID: 37564011 DOI: 10.1002/cam4.6449]

[98] Denaro N, Garrone O, Occelli M, Fea E, Granetto C, et al. Unusual fatal outcome following administration of a combination of anti-PD1 and anti-CTLA4 in metastatic renal cell carcinoma: liver toxicity case report and a literature review. Eur J Case Rep Intern Med 2021; 8(7): 002639. [PMID: 34268267 DOI: 10.12890/2021_002639]

[99] Biewenga M, van der Kooij MK, Wouters MWJM, Aarts MJB, van den Berkmortel FWPJ, et al. Checkpoint inhibitor induced hepatitis and the relation with liver metastasis and outcome in advanced melanoma patients. Hepatol Int 2021; 15(2): 510-9. [PMID: 33634373 DOI: 10.1007/s12072-021-10151-4]

[100] Yang W, Li X, He J, Xuan Q, Si H, et al. Efficacy and safety of immune checkpoint inhibitors combined with anti-VEGF therapy in the treatment of unresectable or advanced liver cancer: a systematic review. Immunopharmacol Immunotoxicol 2023; 45(6): 770-9. [PMID: 37228221 DOI: 10.1080/08923973.2023.2215404]

[101] Danlos FX, Voisin AL, Dyevre V, Michot JM, Routier E, et al. Safety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease. Eur J Cancer 2018; 91: 21-9. [PMID: 29331748 DOI: 10.1016/j.ejca.2017.12.008]

[102] Honma Y, Shibata M, Gohda T, Matsumiya H, Kumamoto K, et al. Rapid progression of liver fibrosis induced by acute liver injury due to immune-related adverse events of atezolizumab. Intern Med 2021; 60(12): 1847-53. [PMID: 33456046 DOI: 10.2169/internalmedicine.6535-20]

[103] De Martin E, Michot JM, Rosmorduc O, Guettier C, Samuel D. Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors. JHEP Rep 2020; 2(6): 100170. [PMID: 33205034 DOI: 10.1016/j.jhepr.2020.100170]

[104] El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017; 389(10088): 2492-502. [PMID: 28434648 DOI: 10.1016/S0140-6736(17)31046-2]

[105] Mok K, Wu C, Chan S, Wong G, Wong VWS, et al. Clinical management of gastrointestinal and liver toxicities of immune checkpoint inhibitors. Clin Colorectal Cancer 2024; 23(1): 4-13. [PMID: 38172003 DOI: 10.1016/j.clcc.2023.12.003]

[106] Zen Y, Yeh MM. Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury. Mod Pathol 2018; 31(6): 965-73. [PMID: 29403081 DOI: 10.1038/s41379-018-0013-y]

[107] Zen Y, Yeh MM. Checkpoint inhibitor-induced liver injury: a novel form of liver disease emerging in the era of cancer immunotherapy. Semin Diagn Pathol 2019; 36(6): 434-40. [PMID: 31358424 DOI: 10.1053/j.semdp.2019.07.009]

[108] Garcia-Neuer M, Marmarelis ME, Jangi SR, Luke JJ, Ibrahim N, et al. Diagnostic comparison of CT scans and colonoscopy for immune-related colitis in ipilimumab-treated advanced melanoma patients. Cancer Immunol Res 2017; 5(4): 286-91. [PMID: 28373217 DOI: 10.1158/2326-6066.CIR-16-0302]

[109] Goel N, Levine MD, Chambers LM, Nagel CI. Gastritis as an immunotherapy-related toxicity in the treatment of endometrial cancer: a case report. Gynecol Oncol Rep 2023; 47: 101174. [PMID: 37102082 DOI: 10.1016/j.gore.2023.101174]

[110] Haryal A, Townsend MJ, Baskaran V, Srivoleti P, Giobbie-Hurder A, et al. Immune checkpoint inhibitor gastritis is often associated with concomitant enterocolitis, which impacts the clinical course. Cancer 2023; 129(3): 367-75. [PMID: 36377339 DOI: 10.1002/cncr.34543]

[111] Nakai M, Kai Y, Suzuki K, Matsuda M, Kikukawa S, et al. A case of perforated immune-related colitis complicated by cytomegalovirus infection during treatment of immune-related adverse effect in lung cancer immunotherapy. Respir Med Case Rep 2023; 41: 101794. [PMID: 36583058 DOI: 10.1016/j.rmcr.2022.101794]

[112] Karamchandani DM, Chetty R. Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists’ perspective. J Clin Pathol 2018; 71(8): 665-71. [PMID: 29703758 DOI: 10.1136/jclinpath-2018-205143]

[113] Jiang C, Tang W, Yang X, Li H. Immune checkpoint inhibitor-related pancreatitis: what is known and what is not. Open Med 2023; 18(1): 20230713. [PMID: 37273919 DOI: 10.1515/med-2023-0713]

[114] de La Rochefoucauld J, Noël N, Lambotte O. Management of immune-related adverse events associated with immune checkpoint inhibitors in cancer patients: a patient-centred approach. Intern Emerg Med 2020; 15(4): 587-98. [PMID: 32144552 DOI: 10.1007/s11739-020-02295-2]

[115] Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol 2017; 35(7): 785-92. [PMID: 28068177 DOI: 10.1200/JCO.2015.66.1389]

[116] Amin A, DePril V, Hamid O, Wolchock J, Maio M, et al. Evaluation of the effect of systemic corticosteroids for the treatment of immune-related adverse events (irAEs) on the development or maintenance of ipilimumab clinical activity. J Clin Oncol 2009; 27(15 suppl): 9037. [DOI: 10.1200/jco.2009.27.15_suppl.9037]

[117] Downey SG, Klapper JA, Smith FO, Yang JC, Sherry RM, et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 2007; 13(22 Pt 1): 6681-8. [PMID: 17982122 DOI: 10.1158/1078-0432.CCR-07-0187]

[118] Harmankaya K, Erasim C, Koelblinger C, Ibrahim R, Hoos A, et al. Continuous systemic corticosteroids do not affect the ongoing regression of metastatic melanoma for more than two years following ipilimumab therapy. Med Oncol 2011; 28(4): 1140- 4. [PMID: 20593249 DOI: 10.1007/s12032-010-9606-0]

[119] Liu SJ, Yan LJ, Wang HC, Ding ZN, Liu H, et al. Safety, efficacy, and survival outcomes of immune checkpoint inhibitors rechallenge in patients with cancer: a systematic review and meta-analysis. Oncologist 2024; 29(11): e1425-34. [PMID: 38940446 DOI: 10.1093/oncolo/oyae134]

[120] Ueno K, Suzuki K, Saito K, Shinohara H, Miura A. Nivolumab rechallenge after immune-related adverse events in patients with unresectable advanced or recurrent esophageal cancer. In Vivo 2024; 38(2): 794-9. [PMID: 38418136 DOI: 10.21873/invivo.13503]

[121] Socinski MA, Jotte RM, Cappuzzo F, Nishio M, Mok TSK, et al. Association of immune-related adverse events with efficacy of atezolizumab in patients with non-small cell lung cancer: pooled analyses of the phase 3 IMpower130, IMpower132, and IMpower150 randomized clinical trials. JAMA Oncol 2023; 9(4): 527-35. [PMID: 36795388 DOI: 10.1001/jamaoncol.2022.7711]

[122] Nasca V, Barretta F, Corti F, Lonardi S, Niger M, et al. Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer. J Immunother Cancer 2023; 11(1): e005493. [PMID: 36593068 DOI: 10.1136/jitc-2022-005493]

[123] Fu J, Li WZ, McGrath NA, Lai CW, Brar G, et al. Immune checkpoint inhibitor associated hepatotoxicity in primary liver cancer versus other cancers: a systematic review and meta-analysis. Front Oncol 2021; 11: 650292. [PMID: 33968750 DOI: 10.3389/fonc.2021.650292]

[124] Gao Y, Xu P, Sun D, Jiang Y, Lin XL, et al. Faecalibacterium prausnitzii abrogates intestinal toxicity and promotes tumor immunity to increase the efficacy of dual CTLA4 and PD-1 checkpoint blockade. Cancer Res 2023; 83(22): 3710-25. [PMID: 37602831 DOI: 10.1158/0008-5472.CAN-23-0605]

[125] Kawano M, Yano Y, Yamamoto A, Yasutomi E, Inoue Y, et al. Risk factors for immune checkpoint inhibitor-induced liver injury and the significance of liver biopsy. Diagnostics (Basel) 2024; 14(8): 815. [PMID: 38667461 DOI: 10.3390/diagnostics14080815]

[126] Weissman S, Saleem S, Sharma S, Krupka M, Inayat F, et al. Incidence, mortality, and risk factors of immunotherapy-associated hepatotoxicity: a nationwide hospitalization analysis. Liver Res 2021; 5(1): 28-32. [PMID: 33828870 DOI: 10.1016/j.livres.2021.01.003]

[127] Chen J, Lin A, Luo P. Advancing pharmaceutical research: a comprehensive review of cutting-edge tools and technologies. Curr Pharm Anal 2024; 21(1): 1-19. [DOI: 10.1016/j.cpan.2024.11.001]

[128] Saleem M, Watson AE, Anwaar A, Jasser AO, Yusuf N. Optimizing immunotherapy: the synergy of immune checkpoint inhibitors with artificial intelligence in melanoma treatment. Biomolecules 2025; 15(4): 589. [PMID: 40305346 DOI: 10.3390/biom15040589]

[129] Zitu MM, Gatti-Mays ME, Johnson KC, Zhang S, Shendre A, et al. Detection of patient-level immunotherapy-related adverse events (irAEs) from clinical narratives of electronic health records: a high-sensitivity artificial intelligence model. Pragmatic Obs Res 2024; 15: 243-52. [PMID: 39720010 DOI: 10.2147/POR.S468253]

[130] Yokode M, Shiokawa M, Kawakami H, Kuwada T, Nishikawa Y, et al. Anti-integrin αvβ6 autoantibodies are a potential biomarker for ulcerative colitis-like immune checkpoint inhibitor-induced colitis. Br J Cancer 2024; 130(9): 1552-60. [PMID: 38461170 DOI: 10.1038/s41416-024-02647-1]

[131] Wang D, Zhao Y, Zeng Y, Hu L, Xu C. Update on immunotherapy-mediated colitis: clinical features, mechanisms, and management. Malig Spectr 2024; 1(4): 225-42. [DOI: 10.1002/msp2.50]

[132] Mallardo D, Fordellone M, Bailey M, White A, Simeone E, et al. Gene-expression signature predicts autoimmune toxicity in metastatic melanoma. J Immunother Cancer 2025; 13(7): e011315. [PMID: 40633934 DOI: 10.1136/jitc-2024-011315]

[133] Nobusawa T, Kaneko S, Murakawa M, Tsuchiya J, Miyoshi M, et al. Immune-related adverse events in patients with low baseline serum IL-6 treated with durvalumab plus tremelimumab for hepatocellular carcinoma: a case series. Clin J Gastroenterol 2025; 18(5): 899-904. [PMID: 40632185 DOI: 10.1007/s12328-025-02176-1]

[134] Cunningham M, Iafolla M, Kanjanapan Y, Cerocchi O, Butler M, et al. Evaluation of liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy. PloS One 2021; 16(6): e0253070. [PMID: 34115819 DOI: 10.1371/journal.pone.0253070]

[135] Lee SK, Choi JY, Jung ES, Kwon JH, Jang JW, et al. An immunological perspective on the mechanism of drug induced liver injury: focused on drugs for treatment of hepatocellular carcinoma and liver transplantation. Int J Mol Sci 2023; 24(5): 5002. [PMID: 36902432 DOI: 10.3390/ijms24055002]

[136] Mayo Clinic . Probiotics preventing immune checkpoint inhibitor-induced colitis. clinicaltrials.gov; 2025 Aug. Report No.: NCT06508034. Available from: https://clinicaltrials.gov/study/NCT06508034

[137] Yang Y. Immune checkpoint inhibitor rechallenge in combination with siltuximab prophylaxis for patients who had prior immune-related adverse event (CIRES Trial). clinicaltrials.gov; 2025 Jan. Report No.: NCT06470971. Available from: https://clinicaltrials.gov/study/NCT06470971

[138] Lozano AX, Chaudhuri AA, Nene A, Bacchiocchi A, Earland N, et al. T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma. Nat Med 2022; 28(2): 353-62. [PMID: 35027754 DOI: 10.1038/s41591-021-01623-z]

[139] He JY, Kim YJ, Mennillo E, Rusu I, Bain J, et al. Dysregulation of CD4⁺ and CD8⁺ resident memory T, myeloid, and stromal cells in steroid-experienced, checkpoint inhibitor colitis. J Immunother Cancer 2024; 12(4): e008628. [PMID: 38642938 DOI: 10.1136/jitc-2023-008628]

[140] Zhai Y, Liang X, Deng M. Myeloid cells meet CD8⁺ T cell exhaustion in cancer: what, why and how. Chin J Cancer Res 2024; 36(6): 616-51. [PMID: 39802897 DOI: 10.21147/j.issn.1000-9604.2024.06.04]

[141] Dubin K, Callahan MK, Ren B, Khanin R, Viale A, et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat Commun 2016; 7: 10391. [PMID: 26837003 DOI: 10.1038/ncomms10391]

[142] Gronke K, Nguyen M, Fuhrmann H, Santamaria de Souza N, Schumacher J, et al. Translocating gut pathobiont Enterococcus gallinarum induces T_H17 and IgG3 anti-RNA-directed autoimmunity in mouse and human. Sci Transl Med 2025; 17(784): eadj6294. [PMID: 39908347 DOI: 10.1126/scitranslmed.adj6294]

[143] Raychaudhuri SP, Raychaudhuri SK. JAK inhibitor: introduction. Indian J Dermatol Venereol Leprol 2023; 89(5): 688-90. [PMID: 37609754 DOI: 10.25259/IJDVL_8_2023]

[144] Liu Q, Liu M, Zou Z, Lin J, Zhang N, et al. Tofacitinib for the treatment of immune-related adverse events in cancer immunotherapy: a multi-center observational study. J Transl Med 2024; 22(1): 803. [PMID: 39210332 DOI: 10.1186/s12967-024-05617-6]

[145] NYU Langone Health . A phase II study of the interleukin-6 receptor inhibitor sarilumab in combination with ipilimumab, nivolumab and relatlimab in patients with unresectable stage III or stage IV melanoma. clinicaltrials.gov; 2025 Feb. Report No.: NCT05428007. Available from: https://clinicaltrials.gov/study/NCT05428007

[146] Mehnert JM, Mehmi I, Goldberg JD, Dimitrova M, Arriola P, et al. A phase II study of the interleukin-6 (IL-6) receptor blocking antibody sarilumab (Sari) in combination with ipilimumab (Ipi), nivolumab (Nivo) and relatlimab (Rela) in patients with unresectable stage III or stage IV melanoma. J Clin Oncol 2025; 43(16 suppl): 9510. [DOI: 10.1200/JCO.2025.43.16_suppl.9510]

[147] Holmstroem RB, Nielsen OH, Jacobsen S, Riis LB, Theile S, et al. COLAR: open-label clinical study of IL-6 blockade with tocilizumab for the treatment of immune checkpoint inhibitor-induced colitis and arthritis. J Immunother Cancer 2022; 10(9): e005111. [PMID: 36096534 DOI: 10.1136/jitc-2022-005111]

[148] Halsey TM, Thomas AS, Hayase T, Ma W, Abu-Sbeih H, et al. Microbiome alteration via fecal microbiota transplantation is effective for refractory immune checkpoint inhibitor-induced colitis. Sci Transl Med 2023; 15(700): eabq4006. [PMID: 37315113 DOI: 10.1126/scitranslmed.abq4006]

[149] Elkrief A, Waters NR, Smith N, Dai A, Slingerland J, et al. Immune-related colitis is associated with fecal microbial dysbiosis and can be mitigated by fecal microbiota transplantation. Cancer Immunol Res 2024; 12(3): 308-21. [PMID: 38108398 DOI: 10.1158/2326-6066.CIR-23-0498]

[150] Wang Y, Varatharajalu K, Shatila M, Campbell MT, Msaouel P, et al. First-line treatment of fecal microbiota transplantation for immune-mediated colitis. J Clin Oncol 2024; 42(16 suppl): 2660. [DOI: 10.14309/01.ajg.0001030568.48967.db]

[151] University of Aarhus. FMT in checkpoint inhibitor-mediated diarrhea and colitis (Immunobiome). clinicaltrials.gov; 2024 Jan. Report No.: NCT06206707. Available from: https://clinicaltrials.gov/study/NCT06206707

[152] Herrera M, Pretelli G, Desai J, Garralda E, Siu LL, et al. Bispecific antibodies: advancing precision oncology. Trends Cancer 2024; 10(10): 893-919. [PMID: 39214782 DOI: 10.1016/j.trecan.2024.07.002]

[153] Dahan R, Korman AJ. Fc-optimized checkpoint antibodies for cancer immunotherapy. Trends Mol Med 2025; 31(6): 501-5. [PMID: 39487064 DOI: 10.1016/j.molmed.2024.10.008]

[154] Naing A, Thistlethwaite F, De Vries EGE, Eskens FALM, Uboha N, et al. CX-072 (pacmilimab), a Probody ® PD-L1 inhibitor, in advanced or recurrent solid tumors (PROCLAIM-CX-072): an open-label dose-finding and first-in-human study. J Immunother Cancer 2021; 9(7): e002447.

[155] Ahmed LA, Al-Massri KF. Gut microbiota modulation for therapeutic management of various diseases: a new perspective using stem cell therapy. Curr Mol Pharmacol 2023; 16(1): 43-59. [PMID: 35196976 DOI: 10.2174/1874467215666220222105004]

[156] Govindan R, Szczesna A, Ahn MJ, Schneider CP, Gonzalez Mella PF, et al. Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol 2017; 35(30): 3449-57.

[157] Baas P, Scherpereel A, Nowak AK, Fujimoto N, Peters S, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet 2021; 397(10272): 375-86. [PMID: 33485464 DOI: 10.1016/S0140-6736(20)32714-8]

[158] Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 2018; 378(22): 2093-104. [PMID: 29658845 DOI: 10.1056/NEJMoa1801946]

[159] O’Byrne KJ, Lee KH, Kim SW, Park K, Nishio M, et al. First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. ESMO Open 2022; 7(1): 100394. [PMID: 35158207 DOI: 10.1016/j.esmoop.2022.100394]

[160] Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol 2016; 17(11): 1558-68. [PMID: 27622997 DOI: 10.1016/S1470-2045(16)30366-7]

[161] Tandon P, Bourassa-Blanchette S, Bishay K, Parlow S, Laurie SA, et al. The risk of diarrhea and colitis in patients with advanced melanoma undergoing immune checkpoint inhibitor therapy: a systematic review and meta-analysis. J Immunother 2018; 41(3): 101-8. [PMID: 29401166 DOI: 10.1097/CJI.0000000000000213]

[162] Felip E, Altorki N, Zhou C, Csőszi T, Vynnychenko I, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet 2021; 398(10308): 1344-57. [PMID: 34555333 DOI: 10.1016/S0140-6736(21)02098-5]

[163] Pujol JL, Greillier L, Audigier-Valette C, Moro-Sibilot D, Uwer L, et al. A randomized non-comparative phase II study of anti-programmed cell death-ligand 1 atezolizumab or chemotherapy as second-line therapy in patients with small cell lung cancer: results from the IFCT-1603 trial. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 2019; 14(5): 903-13. [PMID: 30664989 DOI: 10.1016/j.jtho.2019.01.008]

[164] Seto T, Nosaki K, Shimokawa M, Toyozawa R, Sugawara S, et al. Phase II study of atezolizumab with bevacizumab for non-squamous non-small cell lung cancer with high PD-L1 expression (@Be Study). J Immunother Cancer 2022; 10(2): e004025. [PMID: 35105689 DOI: 10.1136/jitc-2021-004025]

[165] Ready NE, Ott PA, Hellmann MD, Zugazagoitia J, Hann CL, et al. Nivolumab monotherapy and nivolumab plus ipilimumab in recurrent small cell lung cancer: results from the CheckMate 032 randomized cohort. J Thorac Oncol 2020; 15(3): 426-35. [PMID: 31629915 DOI: 10.1016/j.jtho.2019.10.004]

[166] Saowapa S, Polpichai N, Tanariyakul M, Wannaphut C, Wattanachayakul P, et al. Immunotherapy-induced hepatitis in metastatic colorectal cancer: a systematic review and meta-analysis. Proc Bayl Univ Med Cent 2024; 37(5): 841-50. [PMID: 39165807 DOI: 10.1080/08998280.2024.2374161]

[167] Koseki M, Nishimura Y, Elias E, Estaris J, Chesta F, et al. Pancreatitis in patients with cancer receiving immune checkpoint inhibitors: a systematic review and meta-analysis. Target Oncol 2024; 19(6): 867-77. [PMID: 39392549 DOI: 10.1007/s11523-024-01098-1]

[168] Zhang T, Wang Y, Shi C, Liu X, Lv S, et al. Pancreatic injury following immune checkpoint inhibitors: a systematic review and meta-analysis. Front Pharmacol 2022; 13: 955701. [PMID: 36133806 DOI: 10.3389/fphar.2022.955701]