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The precise role of T-cell immunoreceptor with Ig and ITIM domains (TIGIT), an emerging immunosuppressive receptor, in ECCA, and its impact on CD8+\u2009T cell exhaustion (Tex) remains unclear. We performed single-cell RNA sequencing (scRNA-seq) to characterize tumor-infiltrating lymphocytes (TILs) isolated from ECCA. We found that TIGIT was significantly overexpressed in TOX+CD8 T cells. Tissue microarray and immunohistochemistry staining demonstrated that increased TIGIT expression was associated with poorer patient survival. Flow cytometry analysis revealed that TIGIT+CD8+\u2009T cells exhibited decreased TNF-\u03b1, IFN-\u03b3, and TCF-1 expression, accompanied by elevated PD-1 and TIM-3 expression compared to TIGIT\u2212CD8+\u2009T cells. In the patient-derived xenograft (PDX) model, the anti-TIGIT treatment group demonstrated reduced tumor weight, enhanced CD8 frequency, and an increased IFN-\u03b3 proportion compared to the PBS treatment group. The TIGIT antibody-treated group exhibited a notably higher fraction of GRZB, and anti-TIGIT treatment led to elevated TCF-1 protein levels and decreased protein levels of TOX1 and NR4A1. Moreover, TIGIT+CD8 T cells from TILs appear to be in a state of exhaustion with low potential killing capacity in ECCA, as shown by scRNA-seq. Taken together, the present study underscores the significant role of TIGIT in ECCA, contributing to T cell exhaustion and a compromised CD8+\u2009T cell immune response. Targeting TIGIT presents a promising therapeutic avenue to enhance the CD8+\u2009T-cell response, thereby potentially improving ECCA therapeutic benefits.<\/jats:p>","DOI":"10.1038\/s41419-025-07388-4","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T10:03:41Z","timestamp":1739354621000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["TIGIT expression in extrahepatic cholangiocarcinoma and its impact on CD8\u2009+\u2009T cell exhaustion: implications for immunotherapy"],"prefix":"10.1038","volume":"16","author":[{"given":"Tengqian","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lang","family":"Gan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dehong","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8388-7406","authenticated-orcid":false,"given":"Qianfei","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leida","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,12]]},"reference":[{"key":"7388_CR1","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1038\/s41575-020-0310-z","volume":"17","author":"JM Banales","year":"2020","unstructured":"Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, et al. 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