{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T06:16:20Z","timestamp":1783664180484,"version":"3.55.0"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"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. Immunol."],"abstract":"<jats:p>Immune checkpoint inhibitor (ICI) therapy for colorectal cancer (CRC) can be accompanied by endocrine adverse events, yet the comparative risk across commonly used regimens remains unclear. We therefore conducted a network meta-analysis of randomized controlled trials in CRC published up to November 22, 2025, estimating risk ratios (RRs) with 95% confidence intervals (CIs) and assessing risk of bias. Six RCTs were included. Relative to conventional therapy, ICI-based regimens were associated with a higher thyroid-related toxicity burden. Pembrolizumab and ICI+tyrosine kinase inhibitor (TKI) significantly increased the risk of hypothyroidism, whereas hyperthyroidism was significantly higher with ICI+TKI and ICI plus chemotherapy plus an anti-angiogenic antibody (ICI+Chem+Antiangio-Ab). Grade 1\u20132 adverse events were consistently increased across ICI-based treatments. For thyroiditis, diabetes mellitus, adrenal insufficiency, and grade 3\u20134 adverse events, effect estimates were imprecise with wide 95% CIs; nevertheless, SUCRA rankings tended to place ICI+TKI toward the higher-risk end for thyroiditis and diabetes. These findings indicate that ICI-containing strategies in CRC increase risks of endocrine adverse events\u2014particularly for thyroid dysfunction\u2014supporting the need for proactive endocrine monitoring and standardized management, while highlighting the limited precision of current evidence for rarer endpoints and severe toxicity.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>Systematic Review Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/PROSPERO\/view\/CRD42023469312<\/jats:ext-link>\n                      , identifier CRD42023469312.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1798732","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T05:37:34Z","timestamp":1783661854000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A network meta-analysis of endocrine adverse events induced by immune checkpoint inhibitors in colorectal cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Boyu","family":"Chen","sequence":"first","affiliation":[{"name":"Graduate School, Hebei North University","place":["Zhangjiakou, Hebei, China"]},{"name":"Department of Endocrinology, Hebei General Hospital","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Hebei General Hospital","place":["Shijiazhuang, Hebei, China"]},{"name":"Hebei Key Laboratory of Metabolic Diseases","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kexin","family":"Gan","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Hebei General Hospital","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Hebei General Hospital","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine (Clinical Laboratory), Hebei General Hospital","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boqing","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Hebei General Hospital","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anus and Intestine Surgery, Shijiazhuang People's Hospital","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2022-327736","article-title":"Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN","volume":"72","author":"Morgan","year":"2023","journal-title":"Gut"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1186\/s12967-025-06876-7","article-title":"Factors affecting survival in patients with colorectal cancer: an umbrella review","volume":"23","author":"Yu","year":"2025","journal-title":"J Transl Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00600-w","article-title":"Immune-checkpoint inhibitors: long-term implications of toxicity","volume":"19","author":"Johnson","year":"2022","journal-title":"Nat Rev Clin Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.888181","article-title":"Microsatellite instability and metastatic colorectal cancer - a clinical perspective","volume":"12","author":"Buchler","year":"2022","journal-title":"Front Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2017699","article-title":"Pembrolizumab in microsatellite-instability-high advanced colorectal cancer","volume":"383","author":"Andre","year":"2020","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1200\/jco.21.01015","article-title":"First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high\/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study","volume":"40","author":"Lenz","year":"2022","journal-title":"J Clin Oncol Off J Am Soc Clin Oncol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"G1","DOI":"10.1530\/eje-22-0689","article-title":"Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an ESE clinical practice guideline","volume":"187","author":"Husebye","year":"2022","journal-title":"Eur J Endocrinol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.eprac.2024.03.023","article-title":"Endocrinopathies associated with immune checkpoint inhibitor use","volume":"30","author":"Kotwal","year":"2024","journal-title":"Endocrine Pract Off J Am Coll Endocrinol Am Assoc Clin Endocrinologists"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1\u201319","DOI":"10.15212\/amm-2023-0037","article-title":"Endocrine toxicity of immune checkpoint inhibitors: a network meta-analysis of the current evidence","volume":"3","author":"Ouyang","year":"2024","journal-title":"Acta Materia Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: a revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ (Clinical Res Ed)"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2023.2761","article-title":"Avelumab vs standard second-line chemotherapy in patients with metastatic colorectal cancer and microsatellite instability: a randomized clinical trial","volume":"9","author":"Taieb","year":"2023","journal-title":"JAMA Oncol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1038\/s41392-024-01788-2","article-title":"XELOX (capecitabine plus oxaliplatin) plus bevacizumab (anti-VEGF-A antibody) with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer: a multicenter, open-label, randomized, controlled, phase 3 trial","volume":"9","author":"Pan","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.49040","article-title":"Assessment of capecitabine and bevacizumab with or without atezolizumab for the treatment of refractory metastatic colorectal cancer: a randomized clinical trial","volume":"5","author":"Mettu","year":"2022","journal-title":"JAMA Netw Open"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2022.100559","article-title":"MODUL cohort 2: an adaptable, randomized, signal-seeking trial of fluoropyrimidine plus bevacizumab with or without atezolizumab maintenance therapy for BRAF(wt) metastatic colorectal cancer","volume":"7","author":"Tabernero","year":"2022","journal-title":"ESMO Open"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.11.012","article-title":"Pembrolizumab versus chemotherapy in microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer: 5-year follow-up from the randomized phase III KEYNOTE-177 study","volume":"36","author":"Andre","year":"2025","journal-title":"Ann Oncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.02736","article-title":"Lenvatinib plus pembrolizumab versus standard of care for previously treated metastatic colorectal cancer: final analysis of the randomized, open-label, phase III LEAP-017 study","volume":"42","author":"Kawazoe","year":"2024","journal-title":"J Clin Oncol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-020-02355-9","article-title":"Mapping endocrine toxicity spectrum of immune checkpoint inhibitors: a disproportionality analysis using the WHO adverse drug reaction database, VigiBase","volume":"69","author":"Bai","year":"2020","journal-title":"Endocrine"},{"key":"B18","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1186\/s40425-019-0754-2","article-title":"Endocrine toxicity of immune checkpoint inhibitors: a real-world study leveraging US Food and Drug Administration adverse events reporting system","volume":"7","author":"Zhai","year":"2019","journal-title":"J Immunother Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-021-00484-3","article-title":"Endocrine toxicities of immune checkpoint inhibitors","volume":"17","author":"Wright","year":"2021","journal-title":"Nat Rev Endocrinol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1210\/er.2018-00006","article-title":"Endocrine toxicity of cancer immunotherapy targeting immune checkpoints","volume":"40","author":"Chang","year":"2019","journal-title":"Endocr Rev"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1111\/cen.14135","article-title":"Thyroid disorders in programmed death 1 inhibitor-treated patients: is previous therapy with tyrosine kinase inhibitors a predisposing factor","volume":"92","author":"Sbardella","year":"2020","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.4103\/ijem.ijem_47_25","article-title":"Endocrine adverse events of immune checkpoint inhibitors: a comprehensive review","volume":"29","author":"Rajan","year":"2025","journal-title":"Indian J Endocrinol Metab"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1172\/jci168730","article-title":"Translational regulation of SND1 governs endothelial homeostasis during stress","volume":"135","author":"Han","year":"2025","journal-title":"J Clin Invest"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1177\/20503121251358313","article-title":"Glycemic management in patients with immune-related diabetes mellitus: a scoping review","volume":"13","author":"Jiang","year":"2025","journal-title":"SAGE Open Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3390\/curroncol29070370","article-title":"Routine screening for central and primary adrenal insufficiency during immune-checkpoint inhibitor therapy: an endocrinology perspective for oncologists","volume":"29","author":"Druce","year":"2022","journal-title":"Curr Oncol (Toronto Ont)"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2020.100011","article-title":"How we treat endocrine complications of immune checkpoint inhibitors","volume":"6","author":"Paschou","year":"2021","journal-title":"ESMO Open"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2024.1369268","article-title":"Effects of immune checkpoint inhibitor associated endocrinopathies on cancer survival","volume":"15","author":"Yang","year":"2024","journal-title":"Front Endocrinol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.1010279","article-title":"Thyroid-related adverse events induced by immune checkpoint inhibitors","volume":"13","author":"Chera","year":"2022","journal-title":"Front Endocrinol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.1038\/s41467-025-56748-3","article-title":"Regorafenib plus sintilimab as a salvage treatment for microsatellite stable metastatic colorectal cancer: a single-arm, open-label, phase II clinical trial","volume":"16","author":"Liu","year":"2025","journal-title":"Nat Commun"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1798732\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T05:37:35Z","timestamp":1783661855000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1798732\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,10]]},"references-count":29,"alternative-id":["10.3389\/fimmu.2026.1798732"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1798732","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,10]]},"article-number":"1798732"}}