{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T15:47:37Z","timestamp":1782920857638,"version":"3.54.5"},"reference-count":43,"publisher":"SAGE Publications","issue":"4-6","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"Science and Technology Talent Support Program of Shaanxi Provincial People\u2019s Hospital","award":["2022BJ-13"],"award-info":[{"award-number":["2022BJ-13"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antioxidants &amp; Redox Signaling"],"published-print":{"date-parts":[[2026,8,1]]},"abstract":"<jats:sec>\n                    <jats:title>Aims:<\/jats:title>\n                    <jats:p>To investigate the tumor-intrinsic lymphocyte cytosolic protein 2 (LCP2) in esophageal squamous cell carcinoma (ESCA) and its molecular mechanisms in mediating resistance to programmed death-1 (PD-1) therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>The expression of LCP2 in ESCA was analyzed using bioinformatics databases and further verified in clinical specimens. Functional studies employed patient-derived organoid models, xenograft models, and molecular assays to assess the impact of LCP2 knockout or overexpression on macrophage polarization, CD8 + T cell exhaustion, and PD-1 therapy response. Mechanistic investigations included nuclear factor-\u03baB (NF-\u03baB) inhibition, signal transducer and activator of transcription 5A (STAT5A) knockdown, chromatin immunoprecipitation, and dual-luciferase reporter assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      LCP2 was markedly upregulated in ESCA and correlated with advanced stage, lymph node metastasis, and poor survival. Tumor-intrinsic LCP2 expression positively correlated with M2 macrophage polarization and sorted CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell exhaustion. Mechanistically, this association depended on NF-\u03baB pathway activation in EpCAM\n                      <jats:sup>+<\/jats:sup>\n                      tumor fractions, while STAT5A transcriptionally regulates tumor-intrinsic LCP2 expression as an upstream transcription factor. Knockdown of tumor-intrinsic LCP2 or STAT5A in EpCAM\n                      <jats:sup>+<\/jats:sup>\n                      tumor fractions suppressed the secretion of immunosuppressive cytokines and restored effector T cell function of sorted CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells.\n                      <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                      , LCP2 depletion significantly inhibited tumor growth and synergized with PD-1 blockade. This synergistic effect was characterized by reduced tumor volume and increased CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell infiltration. Overexpression of LCP2 reversed these effects, confirming its central role in immune escape.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>\n                      The STAT5A\u2013LCP2\u2013NF-\u03baB axis remodels the immunosuppressive tumor microenvironment to mediate ESCA immune escape and PD-1 resistance. Targeting this regulatory axis provides a novel strategy to overcome immunotherapy resistance in esophageal cancer.\n                      <jats:italic toggle=\"yes\">Antioxid. Redox Signal.<\/jats:italic>\n                      45, 242\u2013264.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/15230864261452393","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T01:54:36Z","timestamp":1779933276000},"page":"242-264","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the STAT5A\u2013LCP2\u2013NF-\u03baB Pathway to Overcome PD-1 Resistance in Esophageal Cancer"],"prefix":"10.1177","volume":"45","author":[{"given":"Yuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Oncology, Shaanxi Provincial People\u2019s Hospital, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunzhi","family":"Dang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Shaanxi Provincial People\u2019s Hospital, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Head and Neck Surgery, Shaanxi Provincial People\u2019s Hospital, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Head and Neck Surgery, Shaanxi Provincial People\u2019s Hospital, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhibin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Transplant Urology, Shaanxi Provincial People\u2019s Hospital, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Head and Neck Surgery, Shaanxi Provincial People\u2019s Hospital, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8667-6908","authenticated-orcid":false,"given":"Kun","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Head and Neck Surgery, Shaanxi Provincial People\u2019s Hospital, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"e_1_3_3_2_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1200652"},{"key":"e_1_3_3_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22136995"},{"key":"e_1_3_3_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.955163"},{"key":"e_1_3_3_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes15020197"},{"key":"e_1_3_3_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-002947"},{"key":"e_1_3_3_7_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.9.5654"},{"key":"e_1_3_3_8_1","doi-asserted-by":"publisher","DOI":"10.5937\/jomb0-47507"},{"key":"e_1_3_3_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/cji.0000000000000479"},{"key":"e_1_3_3_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-019-5391-0"},{"key":"e_1_3_3_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2023.11.003"},{"key":"e_1_3_3_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-025-02375-x"},{"key":"e_1_3_3_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2025.167690"},{"key":"e_1_3_3_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/biology11111575"},{"key":"e_1_3_3_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-015-1376-x"},{"key":"e_1_3_3_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-00850-9"},{"key":"e_1_3_3_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-23-3918"},{"key":"e_1_3_3_18_1","doi-asserted-by":"publisher","DOI":"10.1042\/bsr20230612"},{"key":"e_1_3_3_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-025-01310-w"},{"key":"e_1_3_3_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2025.07.010"},{"key":"e_1_3_3_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09913-z"},{"key":"e_1_3_3_22_1","doi-asserted-by":"publisher","DOI":"10.14740\/jocmr4785"},{"key":"e_1_3_3_23_1","doi-asserted-by":"publisher","DOI":"10.21037\/jgo-22-1005"},{"key":"e_1_3_3_24_1","doi-asserted-by":"publisher","DOI":"10.1089\/jir.2015.0054"},{"key":"e_1_3_3_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1199040"},{"key":"e_1_3_3_26_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.70137"},{"issue":"9","key":"e_1_3_3_27_1","first-page":"5574","article-title":"Identification of useful biomolecular markers in kidney renal clear cell carcinoma: An in silico and in vitro analysis-based study","volume":"15","author":"Sheikh K","year":"2023","unstructured":"Sheikh K, , Memon KN, , Usman H, et al. Identification of useful biomolecular markers in kidney renal clear cell carcinoma: An in silico and in vitro analysis-based study. Am J Transl Res, 2023; 15(9):5574\u20135593.","journal-title":"Am J Transl Res"},{"key":"e_1_3_3_28_1","doi-asserted-by":"publisher","DOI":"10.1089\/scd.2018.0125"},{"key":"e_1_3_3_29_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14112429"},{"key":"e_1_3_3_30_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21871"},{"key":"e_1_3_3_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1025373"},{"key":"e_1_3_3_32_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abl3649"},{"key":"e_1_3_3_33_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci168536"},{"key":"e_1_3_3_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdermsci.2020.07.004"},{"key":"e_1_3_3_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.371062"},{"key":"e_1_3_3_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/dote\/doab063"},{"key":"e_1_3_3_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-67197-3"},{"key":"e_1_3_3_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-49495-4"},{"key":"e_1_3_3_39_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-025-03377-9"},{"key":"e_1_3_3_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-024-06746-y"},{"key":"e_1_3_3_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-52977-0"},{"key":"e_1_3_3_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.519"},{"key":"e_1_3_3_43_1","doi-asserted-by":"publisher","DOI":"10.34133\/bmr.0232"},{"key":"e_1_3_3_44_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1641518"}],"container-title":["Antioxidants &amp; Redox Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/15230864261452393","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/15230864261452393","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/15230864261452393","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T15:09:09Z","timestamp":1782918549000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/15230864261452393"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,27]]},"references-count":43,"journal-issue":{"issue":"4-6","published-print":{"date-parts":[[2026,8,1]]}},"alternative-id":["10.1177\/15230864261452393"],"URL":"https:\/\/doi.org\/10.1177\/15230864261452393","relation":{},"ISSN":["1523-0864","1557-7716"],"issn-type":[{"value":"1523-0864","type":"print"},{"value":"1557-7716","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,27]]}}}