{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T07:12:41Z","timestamp":1771312361802,"version":"3.50.1"},"reference-count":40,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T00:00:00Z","timestamp":1771200000000},"content-version":"vor","delay-in-days":46,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2022J01223"],"award-info":[{"award-number":["2022J01223"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2024J01570"],"award-info":[{"award-number":["2024J01570"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2023J01314"],"award-info":[{"award-number":["2023J01314"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Immunology Research"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>\n                    Continuous antigen exposure initiates the developmental process of CD8+ T cell exhaustion, accompanied by a gradual increase in the expression of inhibitory receptors (IRs). Our previous study conceptualized T cell exhaustion as an over\u2010activation status induced by chronic antigen stimuli. To intervene in the developmental process of CD8+ T cell exhaustion, we adjusted the over\u2010activation status by intermittently blocking T cell activation signals with tacrolimus, a T cell activation inhibitor. Melanoma\u2010bearing mice received intermittent tacrolimus (IT) and\/or programmed cell death 1 (PD1) blockade antibody. Exhaustion phenotype of CD8+ tumor\u2010infiltrating lymphocytes (CD8+TILs) was detected by flow cytometry. The expression levels of IRs (PD1 and CD223), as well as memory markers (Ly108 and CD127), were utilized to demarcate the extent of CD8+TILs exhaustion. Then, tyrosinase\u2010related protein 2 peptide (Trp2\n                    <jats:sub>180\u2013188<\/jats:sub>\n                    ) was used to detect tumor\u2010specific CD8+ TILs. Furthermore, tumor growth rate and tumor weight were also evaluated. We found that IT and\/or PD1 blockade enhanced the infiltration of functional CD8+TILs. The findings demonstrated that both IT therapy and PD1 blockade enhanced the antitumor immunity. Combining IT and PD1 blockade led to a greater reduction in tumor growth rate and tumor weight. IT therapy also improved the response of CD8+TILs to melanoma\u2010specific Trp2\n                    <jats:sub>180\u2013188<\/jats:sub>\n                    peptide. A detailed analysis of the CD8+TILs showed that Ly108 and CD127 reduced dramatically as the expression of PD1 increased. In comparison to PD1 blockade, combined treatment (IT plus PD1 blockade) significantly increased the number of intermediate IRs\u2010expressing CD8+TILs, while reducing the number of high IRs\u2010expressing CD8+TILs. These results indicated that combined treatment enhanced the function and decelerated the increase in IRs expression of CD8+TILs, deferring the developmental process of CD8+TILs exhaustion.\n                  <\/jats:p>","DOI":"10.1155\/jimr\/8444562","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T06:29:08Z","timestamp":1771309748000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intermittent Tacrolimus Treatment Delays CD8+ Tumor\u2010Infiltrating Lymphocyte Exhaustion and Enhances PD1 Blockade Therapy in Melanoma\u2010Bearing Mice"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5579-3169","authenticated-orcid":false,"given":"Darong","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4472-1905","authenticated-orcid":false,"given":"Sisi","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaolong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhisheng","family":"Weng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7452-6319","authenticated-orcid":false,"given":"Junjin","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1674-3397","authenticated-orcid":false,"given":"Zili","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,2,16]]},"reference":[{"key":"e_1_2_13_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14468"},{"key":"e_1_2_13_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.07.016"},{"key":"e_1_2_13_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01131-3"},{"key":"e_1_2_13_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2023.12.006"},{"key":"e_1_2_13_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15050"},{"key":"e_1_2_13_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05257-0"},{"key":"e_1_2_13_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1620498114"},{"key":"e_1_2_13_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3862"},{"key":"e_1_2_13_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.04.014"},{"key":"e_1_2_13_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0312-6"},{"key":"e_1_2_13_11_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-019-0814-7"},{"key":"e_1_2_13_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2035"},{"key":"e_1_2_13_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgac017"},{"key":"e_1_2_13_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.10.008"},{"key":"e_1_2_13_15_2","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-003354"},{"key":"e_1_2_13_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2023.09.001"},{"key":"e_1_2_13_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf0683"},{"key":"e_1_2_13_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgt248"},{"key":"e_1_2_13_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-1759(03)00265-5"},{"key":"e_1_2_13_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2020.112899"},{"key":"e_1_2_13_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.12.021"},{"key":"e_1_2_13_22_2","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-21-0515"},{"key":"e_1_2_13_23_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.715234"},{"key":"e_1_2_13_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adg3868"},{"key":"e_1_2_13_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00889-12"},{"key":"e_1_2_13_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1718217115"},{"key":"e_1_2_13_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.106242"},{"key":"e_1_2_13_28_2","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1158\/0008-5472.CAN-16-1387","article-title":"Lymphocytes 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