{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T04:16:02Z","timestamp":1790136962852,"version":"4.0.1"},"reference-count":48,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"unspecified","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2023A1515111183"],"award-info":[{"award-number":["2023A1515111183"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Nature Science Foundation of China","doi-asserted-by":"crossref","award":["82200612"],"award-info":[{"award-number":["82200612"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Nature Science Foundation of China","doi-asserted-by":"crossref","award":["82303178"],"award-info":[{"award-number":["82303178"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,9,15]]},"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Predicting neoadjuvant immunochemotherapy (NICT) response remains a critical challenge in esophageal squamous cell carcinoma (ESCC) management. While the gut bacteriome\u2019s role in immunotherapy has been established, the mycobiome\u2019s predictive potential remains largely unexplored. This study investigated whether gut fungal signatures could serve as reliable biomarkers for NICT response prediction in patients with ESCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed internal transcribed spacer 2 sequencing on 155 fecal samples from 68 patients with ESCC (pre-NICT and post-NICT) and 19 healthy controls. Patients were stratified by tumor regression grade scores. We analyzed mycobiome-immune marker correlations and developed multilayer perceptron (MLP) models using Boruta feature selection. Performance was validated in 37 independent pretreatment patients. Functional causality was confirmed using\n                      <jats:italic>Candida_boidinii<\/jats:italic>\n                      in syngeneic mouse experiments with anti-programmed cell death protein-1 (PD-1) therapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Patients with ESCC exhibited significant mycobiome dysbiosis compared with healthy controls, characterized by reduced alpha diversity and enrichment of pathogenic fungi including\n                      <jats:italic>s_Rhodotorula_minuta<\/jats:italic>\n                      ,\n                      <jats:italic>s_Actinomucor_elegans<\/jats:italic>\n                      , and\n                      <jats:italic>s_Candida_zeylanoides<\/jats:italic>\n                      . Baseline mycobiome profiles distinguished treatment responders from non-responders before therapy initiation. Responders demonstrated higher fungal diversity, more stable co-occurrence networks, and enrichment of beneficial taxa (\n                      <jats:italic>s_Candida_boidinii<\/jats:italic>\n                      ,\n                      <jats:italic>g_Meyerozyma<\/jats:italic>\n                      ,\n                      <jats:italic>s_Meyerozyma_guilliermondii<\/jats:italic>\n                      ,\n                      <jats:italic>s_Trichosporon_dermatis<\/jats:italic>\n                      ) that correlated with Th1-polarized immunity and elevated cytotoxic markers (interferon-\u03b3, interleukin (IL)-12p70, IL-2). Non-responders harbored immunosuppressive fungi (\n                      <jats:italic>s_Candida_albicans<\/jats:italic>\n                      ,\n                      <jats:italic>s_Candida_parapsilosis<\/jats:italic>\n                      ,\n                      <jats:italic>s_Candida_glabrata<\/jats:italic>\n                      ,\n                      <jats:italic>g_Saccharomyces<\/jats:italic>\n                      ) associated with Th2 skewing and regulatory cytokines (IL-4, IL-10, IL-13). Functional analysis revealed responders exhibited enhanced catabolic pathways and phospholipase activities, while non-responders showed upregulated nucleotide biosynthesis. The MLP model achieved robust discriminative performance (genus-level: training area under the receiver operating characteristic curve (AUC) 98.0%, test AUC 82.9%; species-level: training AUC 87.1%, test AUC 87.4%).\n                      <jats:italic>Candida_boidinii<\/jats:italic>\n                      administration enhanced anti-PD-1 efficacy in mice, validating predicted metabolomic and immune changes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Baseline gut mycobiome signatures predict NICT response in ESCC with high accuracy. Experimental validation confirms functional causality, enabling precision medicine approaches for patient stratification and identifying therapeutic targets.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-011508","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T09:35:16Z","timestamp":1759916116000},"page":"e011508","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Fungal microbiota signatures anticipate neoadjuvant immunochemotherapy outcomes in esophageal cancer"],"prefix":"10.1136","volume":"13","author":[{"given":"Liping","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Guangzhou Key Laboratory of Digestive Diseases, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Mai","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gautam","family":"Sethi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjie","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeheng","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Henan Provincial People's Hospital, Zhengzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lele","family":"Wu","sequence":"additional","affiliation":[{"name":"Integrated Clinical Microecology Center, Shenzhen Hospital, Southern Medical University, Shenzhen, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimin","family":"Han","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Tsinghua University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruijun","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjian","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Guangzhou Key Laboratory of Digestive Diseases, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinying","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9270-9951","authenticated-orcid":false,"given":"Le","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"key":"2025111301351234000_13.10.e011508.1","doi-asserted-by":"publisher","DOI":"10.21147\/j.issn.1000-9604.2021.05.01"},{"key":"2025111301351234000_13.10.e011508.2","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1002\/cam4.3647","article-title":"Esophageal cancer: trends in incidence and mortality in China from 2005 to 2015","volume":"10","author":"He","year":"2021","journal-title":"Cancer Med"},{"key":"2025111301351234000_13.10.e011508.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1112088"},{"key":"2025111301351234000_13.10.e011508.4","doi-asserted-by":"publisher","DOI":"10.1007\/s10388-022-00951-4"},{"key":"2025111301351234000_13.10.e011508.5","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1007\/s10388-022-00934-5","article-title":"Neoadjuvant chemotherapy for locally advanced esophageal cancer comparing cisplatin and 5-fluorouracil versus docetaxel plus cisplatin and 5-fluorouracil: a propensity score matching analysis","volume":"19","author":"Nishiwaki","year":"2022","journal-title":"Esophagus"},{"key":"2025111301351234000_13.10.e011508.6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2032125"},{"key":"2025111301351234000_13.10.e011508.7","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30626-6"},{"key":"2025111301351234000_13.10.e011508.8","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2021-004291","article-title":"Multicenter, single-arm, phase II trial of camrelizumab and chemotherapy as neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma","volume":"10","author":"Liu","year":"2022","journal-title":"J Immunother Cancer"},{"key":"2025111301351234000_13.10.e011508.9","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1002\/ijc.33976","article-title":"Neoadjuvant camrelizumab plus chemotherapy for resectable, locally advanced esophageal squamous cell carcinoma (NIC\u2010ESCC2019): A multicenter, phase 2 study","volume":"151","author":"Liu","year":"2022","journal-title":"Intl Journal of Cancer"},{"key":"2025111301351234000_13.10.e011508.10","doi-asserted-by":"crossref","unstructured":"Schroeder W , Ghadimi MPH , Schloesser H , et al . Long-Term Outcome After Histopathological Complete Response with and Without Nodal Metastases Following Multimodal Treatment of Esophageal Cancer. Ann Surg Oncol 2022. doi:10.1245\/s10434-022-11700-3","DOI":"10.1245\/s10434-022-11700-3"},{"key":"2025111301351234000_13.10.e011508.11","article-title":"Association of Pathologic Complete Response and Long-Term Survival Outcomes Among Patients Treated With Neoadjuvant Chemotherapy or Chemoradiotherapy for NSCLC: A Meta-Analysis","volume":"3","author":"Rosner","year":"2022","journal-title":"JTO Clin Res Rep"},{"key":"2025111301351234000_13.10.e011508.12","doi-asserted-by":"publisher","DOI":"10.1093\/jrr\/rry047"},{"key":"2025111301351234000_13.10.e011508.13","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0066019","article-title":"Archaea and fungi of the human gut microbiome: correlations with diet and bacterial residents","volume":"8","author":"Hoffmann","year":"2013","journal-title":"PLoS One"},{"key":"2025111301351234000_13.10.e011508.14","doi-asserted-by":"crossref","unstructured":"van Woerden HC , Gregory C , Brown R , et al . Differences in fungi present in induced sputum samples from asthma patients and non-atopic controls: a community based case control study. BMC Infect Dis 2013;13. doi:10.1186\/1471-2334-13-69","DOI":"10.1186\/1471-2334-13-69"},{"key":"2025111301351234000_13.10.e011508.15","doi-asserted-by":"publisher","DOI":"10.1111\/myc.13402"},{"key":"2025111301351234000_13.10.e011508.16","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1158\/2326-6066.CIR-23-0592","article-title":"Gut Mycobiota Dysbiosis Is Associated with Melanoma and Response to Anti-PD-1 Therapy","volume":"12","author":"Sz\u00f3stak","year":"2024","journal-title":"Cancer Immunol Res"},{"key":"2025111301351234000_13.10.e011508.17","doi-asserted-by":"crossref","first-page":"13","DOI":"10.3390\/cancers13133149","article-title":"Mycobiome and Cancer: What Is the Evidence?","volume":"13","author":"Vallianou","year":"2021","journal-title":"Cancers (Basel)"},{"key":"2025111301351234000_13.10.e011508.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2022.01.003"},{"key":"2025111301351234000_13.10.e011508.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.07.002"},{"key":"2025111301351234000_13.10.e011508.20","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.00341","article-title":"Optimizing Tumor Microenvironment for Cancer Immunotherapy: \u03b2-Glucan-Based Nanoparticles","volume":"9","author":"Zhang","year":"2018","journal-title":"Front Immunol"},{"key":"2025111301351234000_13.10.e011508.21","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.05.050"},{"key":"2025111301351234000_13.10.e011508.22","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1248\/bpb.30.1384","article-title":"Blocking effect of anti-Dectin-1 antibodies on the anti-tumor activity of 1,3-beta-glucan and the binding of Dectin-1 to 1,3-beta-glucan","volume":"30","author":"Ikeda","year":"2007","journal-title":"Biol Pharm Bull"},{"key":"2025111301351234000_13.10.e011508.23","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1111\/bjd.20626","article-title":"Early melanoma invasivity correlates with gut fungal and bacterial profiles","volume":"186","author":"Vitali","year":"2022","journal-title":"Br J Dermatol"},{"key":"2025111301351234000_13.10.e011508.24","doi-asserted-by":"crossref","DOI":"10.1177\/17562848211047130","article-title":"The role of gut mycobiome in health and diseases","volume":"14","author":"Zhang","year":"2021","journal-title":"Therap Adv Gastroenterol"},{"key":"2025111301351234000_13.10.e011508.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-018-0116-y"},{"key":"2025111301351234000_13.10.e011508.26","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.2000.tb02068.x"},{"key":"2025111301351234000_13.10.e011508.27","doi-asserted-by":"crossref","DOI":"10.3390\/cancers12051326","article-title":"Fungal Gut Microbiota Dysbiosis and Its Role in Colorectal, Oral, and Pancreatic Carcinogenesis","volume":"12","author":"Ka\u017amierczak-Siedlecka","year":"2020","journal-title":"Cancers (Basel)"},{"key":"2025111301351234000_13.10.e011508.28","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-317178"},{"key":"2025111301351234000_13.10.e011508.29","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2015-310746"},{"key":"2025111301351234000_13.10.e011508.30","doi-asserted-by":"publisher","DOI":"10.1172\/JCI90562"},{"key":"2025111301351234000_13.10.e011508.31","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100972"},{"key":"2025111301351234000_13.10.e011508.32","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.06.048"},{"key":"2025111301351234000_13.10.e011508.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.09.015"},{"key":"2025111301351234000_13.10.e011508.34","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s10585-009-9300-9","article-title":"Candida albicans enhances experimental hepatic melanoma metastasis","volume":"27","author":"Rodr\u00edguez-Cuesta","year":"2010","journal-title":"Clin Exp Metastasis"},{"key":"2025111301351234000_13.10.e011508.35","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1080\/22221751.2021.1942228","article-title":"Single-cell immune checkpoint landscape of PBMCs stimulated with Candida albicans","volume":"10","author":"Deng","year":"2021","journal-title":"Emerg Microbes Infect"},{"key":"2025111301351234000_13.10.e011508.36","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.abj6915","article-title":"The Candida albicans toxin candidalysin mediates distinct epithelial inflammatory responses through p38 and EGFR-ERK pathways","volume":"15","author":"Nikou","year":"2022","journal-title":"Sci Signal"},{"key":"2025111301351234000_13.10.e011508.37","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-022-30087-z","article-title":"Candida albicans evades NK cell elimination via binding of Agglutinin-Like Sequence proteins to the checkpoint receptor TIGIT","volume":"13","author":"Charpak-Amikam","year":"2022","journal-title":"Nat Commun"},{"key":"2025111301351234000_13.10.e011508.38","doi-asserted-by":"crossref","DOI":"10.1128\/msphere.00817-21","article-title":"Candida auris Bloodstream Infection Induces Upregulation of the PD-1\/PD-L1 Immune Checkpoint Pathway in an Immunocompetent Mouse Model","volume":"7","author":"Wurster","year":"2022","journal-title":"mSphere"},{"key":"2025111301351234000_13.10.e011508.39","doi-asserted-by":"publisher","DOI":"10.1126\/science.1221789"},{"key":"2025111301351234000_13.10.e011508.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.08.024"},{"key":"2025111301351234000_13.10.e011508.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.08.018"},{"key":"2025111301351234000_13.10.e011508.42","doi-asserted-by":"publisher","DOI":"10.1007\/s10096-017-3085-6"},{"key":"2025111301351234000_13.10.e011508.43","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/s41586-019-1608-2","article-title":"The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL","volume":"574","author":"Aykut","year":"2019","journal-title":"Nature New Biol"},{"key":"2025111301351234000_13.10.e011508.44","doi-asserted-by":"publisher","DOI":"10.1097\/MCG.0000000000000035"},{"key":"2025111301351234000_13.10.e011508.45","doi-asserted-by":"publisher","DOI":"10.3852\/08-173"},{"key":"2025111301351234000_13.10.e011508.46","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13040-021-00241-2","article-title":"LightCUD: a program for diagnosing IBD based on human gut microbiome data","volume":"14","author":"Xu","year":"2021","journal-title":"BioData Min"},{"key":"2025111301351234000_13.10.e011508.47","doi-asserted-by":"crossref","first-page":"2835","DOI":"10.3390\/diagnostics13172835","article-title":"Crohn\u2019s Disease Prediction Using Sequence Based Machine Learning Analysis of Human Microbiome","volume":"13","author":"Unal","year":"2023","journal-title":"Diagnostics (Basel)"},{"key":"2025111301351234000_13.10.e011508.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.09.005"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2025-011508","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T09:35:34Z","timestamp":1763026534000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2025-011508"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10]]},"references-count":48,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10,8]]},"published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1136\/jitc-2025-011508"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2025-011508","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10]]}}}