{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T03:13:51Z","timestamp":1789096431003,"version":"build-2803163510"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Currently, immune checkpoint inhibitors (ICIs) have become a mainstay in treating advanced esophageal cancer (EC), yet the predictive significance of routinely collected clinicopathological characteristics for overall survival (OS) remains uncertain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We searched EMBASE, MEDLINE, Cochrane Library, Web of Science, and\n                      <jats:ext-link>ClinicalTrials.gov<\/jats:ext-link>\n                      for phase III randomized controlled trials (RCTs). Eligible studies reported OS for the overall population and subgroups stratified by various clinicopathological features. Pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 13 phase III RCTs involving 7696 advanced EC patients were included. Pooled analysis showed immunotherapy was associated with favorable outcomes (HR = 0.73; 95% CI, 0.69\u20130.77;\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.001). Although both PD-L1-positive and PD-L1-negative patients can benefit from ICIs, there was a robust PD-L1 expression-treatment interaction (\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>Interaction<\/jats:italic>\n                      <\/jats:sub>\n                      = 0.004). Esophageal squamous cell carcinoma (ESCC; HR = 0.73; 95% CI, 0.64\u20130.84;\n                      <jats:italic>P<\/jats:italic>\n                      = 0.001) patients, but not esophageal adenocarcinoma (EAC; HR = 0.92; 95% CI, 0.76\u20131.13;\n                      <jats:italic>P<\/jats:italic>\n                      = 0.44) patients, experienced survival benefits from immunotherapy. Asian patients derived greater benefits (HR = 0.68; 95% CI, 0.62\u20130.75) than non-Asian patients (HR = 0.81; 95% CI, 0.77\u20130.91;\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>Interaction<\/jats:italic>\n                      <\/jats:sub>\n                      = 0.03). Notably, ICIs conferred consistent OS benefits across most clinicopathological subgroups categorized based on sex, age, body weight, smoking, ECOG performance status, disease stage, number of metastatic organs, and liver\/lung metastasis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Immunotherapy significantly improves outcomes in advanced esophageal cancer. However, for EAC patients, clinicians must thoughtfully evaluate the treatment effectiveness, safety, and patient preferences to provide personalized management. PD-L1 expression and race tend to be associated with better outcomes rather than acting as a standalone indicator for patient stratification. Other routinely evaluated clinicopathological features showed no significant modulating effect on immunotherapy efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic Review Registration<\/jats:title>\n                    <jats:p>Identifier CRD420261348582.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1879335","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:42:43Z","timestamp":1784266963000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Associations of PD-L1 expression status, tumor histology and patient ethnic background with immunotherapy outcomes in patients with advanced esophageal cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Xuehua","family":"Cai","sequence":"first","affiliation":[{"name":"Quanzhou First Hospital Affiliated to Fujian Medical University","place":["Quanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junxing","family":"Xie","sequence":"additional","affiliation":[{"name":"Quanzhou First Hospital Affiliated to Fujian Medical University","place":["Quanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Quanzhou First Hospital Affiliated to Fujian Medical University","place":["Quanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1053\/j.gastro.2017.08.023","article-title":"Epidemiology of esophageal squamous cell carcinoma","volume":"154","author":"Abnet","year":"2018","journal-title":"Gastroenterology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1158\/2159-8290.cd-16-0828","article-title":"Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer","volume":"7","author":"Anagnostou","year":"2017","journal-title":"Cancer Discov."},{"key":"B3","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.2307\/2533446","article-title":"Operating characteristics of a rank correlation test for publication bias","volume":"50","author":"Begg","year":"1994","journal-title":"Biometrics"},{"key":"B4","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1038\/cdd.2013.67","article-title":"Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer","volume":"21","author":"Bracci","year":"2014","journal-title":"Cell Death Differ."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e074962","DOI":"10.1136\/bmj-2023-074962","article-title":"Advances in diagnosis and management of cancer of the esophagus","volume":"385","author":"Deboever","year":"2024","journal-title":"BMJ Clin. Research Ed."},{"key":"B6","doi-asserted-by":"publisher","first-page":"300","DOI":"10.3390\/cancers18020300","article-title":"Clinical trials update in resectable esophageal cancer","volume":"18","author":"Dinerman","year":"2026","journal-title":"Cancers"},{"key":"B7","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1056\/NEJMoa2111380","article-title":"Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma","volume":"386","author":"Doki","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.immuni.2019.12.011","article-title":"Top 10 challenges in cancer immunotherapy","volume":"52","author":"Hegde","year":"2020","journal-title":"Immunity"},{"key":"B9","doi-asserted-by":"publisher","first-page":"d5928","DOI":"10.1136\/bmj.d5928","article-title":"The cochrane collaboration's tool for assessing risk of bias in randomised trials","volume":"343","author":"Higgins","year":"2011","journal-title":"BMJ Clin. Research Ed."},{"key":"B10","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/s1470-2045(25)00401-2","article-title":"Tiragolumab plus atezolizumab and chemotherapy as first-line treatment for patients with unresectable oesophageal squamous cell carcinoma (Skyscraper-08): a randomised, double-blind, placebo-controlled, phase 3 trial","volume":"27","author":"Hsu","year":"2026","journal-title":"Lancet Oncol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1016\/s1470-2045(20)30110-8","article-title":"Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (escort): a multicentre, randomised, open-label, phase 3 study","volume":"21","author":"Huang","year":"2020","journal-title":"Lancet Oncol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1506","DOI":"10.1016\/s1470-2045(19)30626-6","article-title":"Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (Attraction-3): a multicentre, randomised, open-label, phase 3 trial","volume":"20","author":"Kato","year":"2019","journal-title":"Lancet Oncol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e7235","DOI":"10.1002\/cam4.7235","article-title":"Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (checkmate 648): 29-month Follow-up from a randomized","volume":"13","author":"Kato","year":"2024","journal-title":"Open-Label, Phase Iii Trial"},{"key":"B14","doi-asserted-by":"publisher","first-page":"4138","DOI":"10.1200\/jco.20.01888","article-title":"Randomized phase iii Keynote-181 study of pembrolizumab versus chemotherapy in advanced esophageal cancer","volume":"38","author":"Kojima","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2383","DOI":"10.1016\/s0140-6736(17)31462-9","article-title":"Oesophageal cancer","volume":"390","author":"Lagergren","year":"2017","journal-title":"Oesophageal Cancer."},{"key":"B16","doi-asserted-by":"publisher","first-page":"535","DOI":"10.21147\/j.issn.1000-9604.2021.05.01","article-title":"Esophageal cancer: epidemiology, risk factors and screening","volume":"33","author":"Li","year":"2021","journal-title":"Chin. J. Cancer Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1038\/s41591-024-02797-y","article-title":"First-line sugemalimab with chemotherapy for advanced esophageal squamous cell carcinoma: a randomized phase 3 study","volume":"30","author":"Li","year":"2024","journal-title":"Nat. Medicine"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e068714","DOI":"10.1136\/bmj-2021-068714","article-title":"Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (Orient-15): Multicentre, randomised, double blind, phase 3 trial","volume":"377","author":"Lu","year":"2022","journal-title":"BMJ Clin. Research Ed."},{"key":"B19","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1001\/jama.2021.12836","article-title":"Effect of camrelizumab Vs placebo added to chemotherapy on survival and progression-free survival in patients with advanced or metastatic esophageal squamous cell carcinoma: the Escort-1st randomized clinical trial","volume":"326","author":"Luo","year":"2021","journal-title":"Jama"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.1186\/s12885-025-15090-z","article-title":"Integrated bioinformatics analysis of differences between eac and escc","volume":"25","author":"Lyu","year":"2025","journal-title":"BMC Cancer"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1679365","DOI":"10.3389\/fimmu.2025.1679365","article-title":"Advancing immunotherapy for esophageal cancer: decoding the roles of Pd-L1, tme, and tumor-intrinsic biomarkers","volume":"16","author":"Ma","year":"2025","journal-title":"Front. Immunology"},{"key":"B22","doi-asserted-by":"publisher","first-page":"105854","DOI":"10.1016\/j.esmoop.2025.105854","article-title":"Pembrolizumab plus chemotherapy versus chemotherapy for advanced esophageal cancer: 5-year extended Follow-up for the randomized phase iii Keynote-590 study","volume":"10","author":"Metges","year":"2025","journal-title":"ESMO Open"},{"key":"B23","doi-asserted-by":"publisher","first-page":"3277","DOI":"10.1158\/1078-0432.Ccr-21-0985","article-title":"Three-year Follow-up and response-survival relationship of nivolumab in previously treated patients with advanced esophageal squamous cell carcinoma (Attraction-3)","volume":"28","author":"Okada","year":"2022","journal-title":"Clin Cancer Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"105906","DOI":"10.1016\/j.ijsu.2021.105906","article-title":"The prisma 2020 statement: an updated guideline for reporting systematic reviews","volume":"88","author":"Page","year":"2021","journal-title":"Int. Journal Surgery Lond. Engl."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/17474124.2026.2646298","article-title":"Clinical role of Anti-Pd-1 immunotherapies in esophageal cancer","volume":"20","author":"Sano","year":"2026","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"3065","DOI":"10.1200\/jco.21.01926","article-title":"Tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (Rationale-302): a randomized phase iii study","volume":"40","author":"Shen","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"10","DOI":"10.3322\/caac.21871","article-title":"A Cancer Journal Clinicians","author":"Siegel","year":"2025"},{"key":"B28","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.semradonc.2006.09.007","article-title":"Are squamous and adenocarcinomas of the esophagus the same disease?","volume":"17","author":"Siewert","year":"2007","journal-title":"Semin. Radiat. Oncol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/s41591-022-02179-2","article-title":"First-line serplulimab or placebo plus chemotherapy in Pd-L1-Positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial","volume":"29","author":"Song","year":"2023","journal-title":"Nat. Medicine"},{"key":"B30","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1016\/s0140-6736(21)01234-4","article-title":"Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (Keynote-590): a randomised, placebo-controlled, phase 3 study","volume":"398","author":"Sun","year":"2021","journal-title":"Lancet"},{"key":"B31","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1007\/s12029-026-01427-9","article-title":"The role of Pd-L1 expression as a predictive biomarker in esophageal cancer: a meta-analysis","volume":"57","author":"Theophilus","year":"2026","journal-title":"J. Gastrointestinal Cancer"},{"key":"B32","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.ccell.2022.02.007","article-title":"Toripalimab plus chemotherapy in treatment-na\u00efve, advanced esophageal squamous cell carcinoma (Jupiter-06): a multi-center phase 3 trial","volume":"40","author":"Wang","year":"2022","journal-title":"Cancer Cell"},{"key":"B33","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/s1470-2045(23)00108-0","article-title":"Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (Rationale-306): a global, randomised, placebo-controlled, phase 3 study","volume":"24","author":"Xu","year":"2023","journal-title":"Lancet Oncol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1016\/j.apsb.2021.09.028","article-title":"Comparative genomic analysis of esophageal squamous cell carcinoma and adenocarcinoma: new opportunities towards molecularly targeted therapy","volume":"12","author":"Zhang","year":"2022","journal-title":"Acta Pharmaceutica Sin. B"},{"key":"B35","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1080\/1744666x.2024.2368194","article-title":"Advancements in immunotherapy for advanced esophageal squamous cell carcinoma: a comprehensive review of current strategies and future directions","volume":"20","author":"Zhang","year":"2024","journal-title":"Expert Rev. Clin. Immunol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"107799","DOI":"10.1016\/j.lungcan.2024.107799","article-title":"Is neoadjuvant immunotherapy necessary in patients with programmed death ligand 1 expression-negative resectable non-small cell lung cancer? A systematic review and meta-analysis","volume":"191","author":"Zhang","year":"2024","journal-title":"Lung Cancer"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1758835920937612","DOI":"10.1177\/1758835920937612","article-title":"Efficacy of Pd-1\/Pd-L1 blockade monotherapy in clinical trials","volume":"12","author":"Zhao","year":"2020","journal-title":"Ther. Adv. Med. Oncol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"189572","DOI":"10.1016\/j.bbcan.2026.189572","article-title":"Current research status and challenges of neoadjuvant immunotherapy for esophageal squamous cell carcinoma","volume":"1881","author":"Zhao","year":"2026","journal-title":"Biochim. Biophys. Acta - Rev. Cancer."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1879335\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:42:45Z","timestamp":1784266965000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1879335\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,17]]},"references-count":38,"alternative-id":["10.3389\/fphar.2026.1879335"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1879335","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,17]]},"article-number":"1879335"}}