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Letter to the Editor Name of Journal: World Journal of Gastroenterology Manuscript Type: LETTER TO THE EDITOR Managing Immune Checkpoint Inhibitor-Associated Gastritis: Insights and Strategies Li-Li Yu, Zhilin He, Xinlai Qian Li-Li Yu, Zhilin He, Xinlai Qian School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, Henan Province, China; The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang Medical University, Xinxiang453003, Henan, China. Supported by This work was supported by grants from the National Natural Science Foundation of China (81671226), Natural Science Foundation of Henan Province (232300421047), Science and Technology Innovation Talents in Universities of Henan Province (24HASTIT067), and Henan Province Young and Middle-aged Health Science and Technology Innovation Talent Project (JQRC2023001). Corresponding author ：Lili Yu, PhD Mailing address: School of Basic Medical Sciences, Xinxiang Medical University, #601 Jinsui Road, Xinxiang, Henan, P.R. China 453003 Contact Number: Tel: +86-373-3831165 Fax: +86-373-3029887 E-mail address: merrys222@126.com Abstract Immune checkpoint inhibitors (ICIs) are widely used due to their effectiveness in treating various tumors. Immune-related adverse events (irAEs) are defined as adverse effects resulting from ICI treatment. Gastrointestinal irAEs are a common type of irAEs characterized by intestinal side effects, such as diarrhea and colitis, which may lead to the discontinuation of ICIs. Key words: Immunotherapy, Immune checkpoint inhibitor, Immune checkpoint inhibitor-related gastritis Core tip: Immune checkpoint inhibitor (ICI)-related gastritis is rare but may lead to serious complications such as gastrorrhagia. The strategies such as early identification, pathological diagnosis, management interventions, and immunotherapy reactivation are discussed to enable clinicians to better manage irAE gastritis and improve the prognosis of these patients. TO THE EDITOR I am writing to express my concern regarding the recently published paper titled “Immune checkpoint inhibitor-associated gastritis: Patterns and management” by Jing Lin, Zhong-Qiao Lin et al in the World Journal of Gastroenterology. In this manuscript, the authors systematically summarize the occurrence patterns and management strategies of immune checkpoint inhibitor-associated gastritis, which provides important evidence for research and practice in this field. Over the last decade, the emergence of immune check-point inhibitor (ICI) therapy has revolutionized the treatment of a growing number of malignancies.[1] Immune-related adverse events (irAE) refer to a set of side-effects in the patients receiving ICIs similar to autoimmune responses.[2] ICI-related gastritis is rare but may lead to serious complications such as gastrorrhagia. The most common abnormality reported on endoscopy is erythema followed by erosions. Other findings like granularity, sloughing, exudates, ulcer, atrophy, and rarely, severe hemorrhagic gastritis, have been reported. [3-5] A common mechanism by which ICIs exert their effects involves activation of effector T cells by inhibition of PD-1, PD-L1, and CTLA-4.[6] It is also proposed that the proliferation of activated T cells and increase in cytokine production, caused by a lack of self-tolerance, may result in irAEs.[7, 8] However，the detailed mechanisms underlying manifestation of irAEs remain unclear. Therefore, the treatment decisions for ICI-related gastritis are based on individual clinical presentations. However, the article does not adequately address individualized treatment options for different patient populations. Considering the patient's immune status, gastritis severity and other factors, the formulation of individualized treatment plan is particularly important. For example，in patients with a personal or familial history of autoimmune disease, or in those who presented signs or symptoms suggestive of an underlying autoimmune disease, screening for autoantibodies may be considered before starting an ICI as these patients have an enhanced risk of developing a full auto­immune disease after treatment.[9] Second, the article fails to mention the evaluation and monitoring strategies prior to immune checkpoint inhibitor therapy when discussing preventive measures, which are important for reducing the risk of gastritis. In addition, the problem of re-provocation after ICI treatment should be focused. Paticularly the risk of recurrence of gastritis needs to be carefully considered. After the complete resolution of irAEs, resumption of immunotherapy is of crucial importance for treatment and prognosis for patients, as is the risk of relapse of irAEs. In the future, we need to continue to deepen our understanding of irAE gastritis, so as to diagnose and treat it appropriately in a timely manner and provide guidance for clinicians in the treatment of ICI-related gastritis and improve the prognosis of patients. REFERENCES 1. Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer, 2012. 12(4): p. 252-264. 2. Zhou, X., et al., Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis. BMC Med, 2020. 18(1): p. 87. 3. Rao, B.B., S. Robertson, and J. Philpott, Checkpoint Inhibitor-Induced Hemorrhagic Gastritis with Pembrolizumab. Am J Gastroenterol, 2019. 114(2): p. 196. 4. Nishimura, Y., et al., Severe Gastritis after Administration of Nivolumab and Ipilimumab. Case Rep Oncol, 2018. 11(2): p. 549-556. 5. Kobayashi, M., et al., Acute hemorrhagic gastritis after nivolumab treatment. Gastrointest Endosc, 2017. 86(5): p. 915-916. 6. Chan, K.K. and A.R. Bass, Autoimmune complications of immunotherapy: pathophysiology and management. Bmj, 2020. 369: p. m736. 7. Ribas, A. and J.D. Wolchok, Cancer immunotherapy using checkpoint blockade. Science, 2018. 359(6382): p. 1350-1355. 8. Postow, M.A., R. Sidlow, and M.D. Hellmann, Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med, 2018. 378(2): p. 158-168. 9. Ramos-Casals, M., et al., Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers, 2020. 6(1): p. 38. Footnotes Conflict-of-interest statement: The authors declare no conflicts of interest.

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