{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:11:19Z","timestamp":1785431479484,"version":"3.56.0"},"reference-count":33,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82403870"],"award-info":[{"award-number":["82403870"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82403870"],"award-info":[{"award-number":["82403870"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Rapid Response Project of Air Force Medical Center","award":["2024ZXKXKT039"],"award-info":[{"award-number":["2024ZXKXKT039"]}]},{"name":"Boost Program of Air Force Medical Center","award":["2025RCZZ11"],"award-info":[{"award-number":["2025RCZZ11"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Chimeric antigen receptor (CAR)-T therapy has achieved partial therapeutic efficacy in solid tumors, but its overall effectiveness remains limited. IL-21-armored CD276.CAR-T (IL21.CD276.CAR-T) represents a promising strategy to enhance anti-tumor activity against esophageal squamous cell carcinoma (ESCC). However, resistance mechanisms remain unclear. We generated IL21.CD276.CAR-T cells and evaluated their cytotoxicity in vitro and in B-NDG xenograft models. Poliovirus receptor (PVR) expression on ESCC cells was analyzed, and shRNA-mediated PVR knockdown was performed to validate its role in resistance. IL-21R expression on ESCC cells was examined to exclude direct IL-21 signaling. IL-21 enhances the cytotoxicity of CD276.CAR-T cells against ESCC. Although IL21.CD276.CAR-T exhibited potent cytotoxicity in vitro, it failed to achieve complete tumor regression, and resistant cells still emerged. Mechanistically, resistance was not caused by CD276 antigen loss or IL-21R expression, but by upregulation of PVR on cancer cell membrane after IL21.CAR-T exposure. PVR knockdown restored CAR-T sensitivity in vitro, enhanced the anti-tumor capacity of IL21.CD276.CAR-T cells, and partially improved anti-tumor efficacy in vivo without systemic toxicity. PVR may act as a mediator of resistance to IL21.CD276.CAR-T in ESCC. Targeting PVR represents a novel strategy to overcome IL21.CAR-T resistance and improve therapeutic outcomes in ESCC.<\/jats:p>","DOI":"10.3390\/ijms27156725","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T07:55:41Z","timestamp":1785225341000},"page":"6725","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PVR Mediates Resistance to IL21.CD276.CAR-T Therapy in Esophageal Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"27","author":[{"given":"Lihong","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Oncology, Air Force Medical Center, People\u2019s Liberation Army, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qijing","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Oncology, Air Force Medical Center, People\u2019s Liberation Army, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenkai","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Oncology, Air Force Medical Center, People\u2019s Liberation Army, Beijing 100142, China"},{"name":"School of Medicine, Northwest University, Xi\u2019an 710069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxuan","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Oncology, Air Force Medical Center, People\u2019s Liberation Army, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Oncology, Air Force Medical Center, People\u2019s Liberation Army, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Oncology, Air Force Medical Center, People\u2019s Liberation Army, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Oncology, Air Force Medical Center, People\u2019s Liberation Army, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Air Force Medical Center, People\u2019s Liberation Army, Beijing 100036, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Oncology, Air Force Medical Center, People\u2019s Liberation Army, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, City University of Hong Kong, Kowloon, Hong Kong SAR 999077, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Air Force Medical Center, People\u2019s Liberation Army, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1002\/cac2.12645","article-title":"Current status and perspectives of esophageal cancer: A comprehensive review","volume":"45","author":"Jiang","year":"2024","journal-title":"Cancer Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e47981","DOI":"10.1097\/MD.0000000000047981","article-title":"Beneficial subgroups for PD-1 inhibitor plus chemotherapy in first-line treatment of advanced esophageal squamous cell carcinoma: A systematic review and meta-analysis","volume":"105","author":"Gao","year":"2026","journal-title":"Medicine"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Zhang, P., Li, X.M., Zhao, X.K., Song, X., Yuan, L., Shen, F.F., Fan, Z.M., and Wang, L.D. 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