{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:31:55Z","timestamp":1790742715013,"version":"4.1.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"name":"the Special Clinical Research Project of the Health Industry of the Shanghai Municipal Health Commission","award":["20224Y0075"],"award-info":[{"award-number":["20224Y0075"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Immunol Immunother"],"DOI":"10.1007\/s00262-026-04366-3","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T11:54:59Z","timestamp":1775130899000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Repurposing rosmarinic acid as an anti-colorectal cancer agent through bolstering T cell anti-tumor immunity by enhancing activation of MEK1-mediated TCR signaling"],"prefix":"10.1007","volume":"75","author":[{"given":"Zhengchun","family":"Kang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuzhu","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feihu","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"4366_CR1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2022110636","volume":"41","author":"Q Wang","year":"2022","unstructured":"Wang Q et al (2022) Disulfiram bolsters T-cell anti-tumor immunity through direct activation of LCK-mediated TCR signaling. EMBO J 41:e110636. https:\/\/doi.org\/10.15252\/embj.2022110636","journal-title":"EMBO J"},{"key":"4366_CR2","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1038\/nature25016","volume":"552","author":"Z Skrott","year":"2017","unstructured":"Skrott Z et al (2017) Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature 552:194\u2013199. https:\/\/doi.org\/10.1038\/nature25016","journal-title":"Nature"},{"key":"4366_CR3","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1038\/s41586-023-06749-3","volume":"623","author":"H Fan","year":"2023","unstructured":"Fan H et al (2023) Trans-vaccenic acid reprograms CD8(+) T cells and anti-tumour immunity. Nature 623:1034\u20131043. https:\/\/doi.org\/10.1038\/s41586-023-06749-3","journal-title":"Nature"},{"key":"4366_CR4","doi-asserted-by":"publisher","DOI":"10.1126\/science.abj3510","author":"M Al-Habsi","year":"2022","unstructured":"Al-Habsi M et al (2022) Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice. Science. https:\/\/doi.org\/10.1126\/science.abj3510","journal-title":"Science"},{"key":"4366_CR5","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aad7118","volume":"8","author":"W Zou","year":"2016","unstructured":"Zou W, Wolchok JD, Chen L (2016) PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med 8:328rv324. https:\/\/doi.org\/10.1126\/scitranslmed.aad7118","journal-title":"Sci Transl Med"},{"key":"4366_CR6","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1038\/nrclinonc.2016.25","volume":"13","author":"DN Khalil","year":"2016","unstructured":"Khalil DN, Smith EL, Brentjens RJ, Wolchok JD (2016) The future of cancer treatment: Immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol 13:273\u2013290. https:\/\/doi.org\/10.1038\/nrclinonc.2016.25","journal-title":"Nat Rev Clin Oncol"},{"key":"4366_CR7","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1038\/nri3403","volume":"13","author":"RJ Brownlie","year":"2013","unstructured":"Brownlie RJ, Zamoyska R (2013) T cell receptor signalling networks: Branched, diversified and bounded. Nat Rev Immunol 13:257\u2013269. https:\/\/doi.org\/10.1038\/nri3403","journal-title":"Nat Rev Immunol"},{"key":"4366_CR8","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1038\/nature11699","volume":"493","author":"X Shi","year":"2013","unstructured":"Shi X et al (2013) Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids. Nature 493:111\u2013115. https:\/\/doi.org\/10.1038\/nature11699","journal-title":"Nature"},{"key":"4366_CR9","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1038\/nri1330","volume":"4","author":"RT Abraham","year":"2004","unstructured":"Abraham RT, Weiss A (2004) Jurkat T cells and development of the T-cell receptor signalling paradigm. Nat Rev Immunol 4:301\u2013308. https:\/\/doi.org\/10.1038\/nri1330","journal-title":"Nat Rev Immunol"},{"key":"4366_CR10","doi-asserted-by":"publisher","first-page":"123","DOI":"10.4049\/jimmunol.133.1.123","volume":"133","author":"A Weiss","year":"1984","unstructured":"Weiss A, Wiskocil RL, Stobo JD (1984) The role of T3 surface molecules in the activation of human T cells: A two-stimulus requirement for IL 2 production reflects events occurring at a pre-translational level. J Immunol 133:123\u2013128","journal-title":"J Immunol"},{"key":"4366_CR11","doi-asserted-by":"publisher","first-page":"1709","DOI":"10.1084\/jem.152.6.1709","volume":"152","author":"S Gillis","year":"1980","unstructured":"Gillis S, Watson J (1980) Biochemical and biological characterization of lymphocyte regulatory molecules. V. Identification of an interleukin 2-producing human leukemia T cell line. J Exp Med 152:1709\u20131719. https:\/\/doi.org\/10.1084\/jem.152.6.1709","journal-title":"J Exp Med"},{"key":"4366_CR12","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1016\/j.trecan.2017.06.007","volume":"3","author":"C Verbaanderd","year":"2017","unstructured":"Verbaanderd C, Meheus L, Huys I, Pantziarka P (2017) Repurposing drugs in oncology: Next steps. Trends Cancer 3:543\u2013546. https:\/\/doi.org\/10.1016\/j.trecan.2017.06.007","journal-title":"Trends Cancer"},{"key":"4366_CR13","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2018.1512456","volume":"8","author":"P Yue","year":"2019","unstructured":"Yue P et al (2019) BRAF and MEK inhibitors differentially affect nivolumab-induced T cell activation by modulating the TCR and AKT signaling pathways. Oncoimmunology 8:e1512456. https:\/\/doi.org\/10.1080\/2162402X.2018.1512456","journal-title":"Oncoimmunology"},{"key":"4366_CR14","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1016\/j.immuni.2016.01.024","volume":"44","author":"PJR Ebert","year":"2016","unstructured":"Ebert PJR et al (2016) MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 44:609\u2013621. https:\/\/doi.org\/10.1016\/j.immuni.2016.01.024","journal-title":"Immunity"},{"key":"4366_CR15","doi-asserted-by":"publisher","first-page":"870","DOI":"10.1002\/eji.200323010","volume":"33","author":"J Won","year":"2003","unstructured":"Won J et al (2003) Rosmarinic acid inhibits TCR-induced T cell activation and proliferation in an Lck-dependent manner. Eur J Immunol 33:870\u2013879. https:\/\/doi.org\/10.1002\/eji.200323010","journal-title":"Eur J Immunol"},{"key":"4366_CR16","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.molimm.2024.05.007","volume":"171","author":"ZS Yun","year":"2024","unstructured":"Yun ZS et al (2024) Rosmarinic acid activates the Ras\/Raf\/MEK\/ERK signaling pathway to regulate CD8+ T cells and autophagy to clear Chlamydia trachomatis in reproductive tract-infected mice. Mol Immunol 171:105\u2013114. https:\/\/doi.org\/10.1016\/j.molimm.2024.05.007","journal-title":"Mol Immunol"},{"key":"4366_CR17","doi-asserted-by":"publisher","first-page":"3534","DOI":"10.1182\/blood-2002-07-1992","volume":"101","author":"MA Kang","year":"2003","unstructured":"Kang MA, Yun SY, Won J (2003) Rosmarinic acid inhibits Ca2+-dependent pathways of T-cell antigen receptor-mediated signaling by inhibiting the PLC-\u03b31 and Itk activity. Blood 101:3534\u20133542. https:\/\/doi.org\/10.1182\/blood-2002-07-1992","journal-title":"Blood"},{"key":"4366_CR18","doi-asserted-by":"publisher","first-page":"e202301739","DOI":"10.1002\/cbdv.202301739","volume":"21","author":"A Imraish","year":"2024","unstructured":"Imraish A et al (2024) Anti-Inflammatory and Antioxidant Effects of Rosmarinic Acid Trimetallic (Cu(0.5)Zn(05.)Fe(2)O(4)) Nanoparticles. Chem Biodivers 21:e202301739. https:\/\/doi.org\/10.1002\/cbdv.202301739","journal-title":"Chem Biodivers"},{"key":"4366_CR19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2021.174119","volume":"902","author":"I Radziejewska","year":"2021","unstructured":"Radziejewska I, Supruniuk K, Bielawska A (2021) Anti-cancer effect of combined action of anti-MUC1 and rosmarinic acid in AGS gastric cancer cells. Eur J Pharmacol 902:174119. https:\/\/doi.org\/10.1016\/j.ejphar.2021.174119","journal-title":"Eur J Pharmacol"},{"key":"4366_CR20","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1016\/j.cell.2015.11.031","volume":"163","author":"B Shen","year":"2015","unstructured":"Shen B (2015) A new golden age of natural products drug discovery. Cell 163:1297\u20131300. https:\/\/doi.org\/10.1016\/j.cell.2015.11.031","journal-title":"Cell"},{"key":"4366_CR21","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202300594","volume":"19","author":"Y Zhou","year":"2023","unstructured":"Zhou Y et al (2023) Rosmarinic acid-crosslinked supramolecular nanoassembly with self-regulated photodynamic and anti-metastasis properties for synergistic photoimmunotherapy. Small 19:e2300594. https:\/\/doi.org\/10.1002\/smll.202300594","journal-title":"Small"},{"key":"4366_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-025-03315-8","author":"S Hao","year":"2025","unstructured":"Hao S et al (2025) PD-1 inhibitor improves radiosensitivity by tumor vessel normalization. Br J Cancer. https:\/\/doi.org\/10.1038\/s41416-025-03315-8","journal-title":"Br J Cancer"},{"key":"4366_CR23","doi-asserted-by":"publisher","DOI":"10.1021\/acsami.5c20577","author":"J Ma","year":"2025","unstructured":"Ma J et al (2025) Functionalized biomimetic carrier-free metal-coordinated nanoplatform for multidimensional synergistic therapy of breast cancer. ACS Appl Mater Interfaces. https:\/\/doi.org\/10.1021\/acsami.5c20577","journal-title":"ACS Appl Mater Interfaces"},{"key":"4366_CR24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1663502","volume":"16","author":"Y Zheng","year":"2025","unstructured":"Zheng Y et al (2025) Impact of MEK inhibition on T-cell infiltration and function after radiotherapy in KRAS-mutant lung cancer. Front Immunol 16:1663502. https:\/\/doi.org\/10.3389\/fimmu.2025.1663502","journal-title":"Front Immunol"},{"key":"4366_CR25","doi-asserted-by":"publisher","DOI":"10.1111\/imr.13436","volume":"329","author":"A Vervaeke","year":"2025","unstructured":"Vervaeke A, Lamkanfi M (2025) MAP kinase signaling at the crossroads of inflammasome activation. Immunol Rev 329:e13436. https:\/\/doi.org\/10.1111\/imr.13436","journal-title":"Immunol Rev"},{"key":"4366_CR26","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1007\/s10875-006-9057-8","volume":"27","author":"YG Hur","year":"2007","unstructured":"Hur YG, Suh CH, Kim S, Won J (2007) Rosmarinic acid induces apoptosis of activated t cells from rheumatoid arthritis patients via mitochondrial pathway. J Clin Immunol 27:36\u201345. https:\/\/doi.org\/10.1007\/s10875-006-9057-8","journal-title":"J Clin Immunol"},{"key":"4366_CR27","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1038\/s12276-020-0435-8","volume":"52","author":"JR Hwang","year":"2020","unstructured":"Hwang JR, Byeon Y, Kim D, Park SG (2020) Recent insights of t cell receptor-mediated signaling pathways for t cell activation and development. Exp Mol Med 52:750\u2013761. https:\/\/doi.org\/10.1038\/s12276-020-0435-8","journal-title":"Exp Mol Med"},{"key":"4366_CR28","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.10134","author":"KA Allison","year":"2016","unstructured":"Allison KA et al (2016) Affinity and dose of TCR engagement yield proportional enhancer and gene activity in CD4+ T cells. Elife. https:\/\/doi.org\/10.7554\/eLife.10134","journal-title":"Elife"},{"key":"4366_CR29","doi-asserted-by":"publisher","first-page":"2593198","DOI":"10.1080\/07853890.2025.2593198","volume":"57","author":"M Jovanovic","year":"2025","unstructured":"Jovanovic M et al (2025) Dual targeting of PD-1\/PD-L1 and iL-33\/ST2 signalling pathways: a promising approach in breast cancer immunotherapy. Ann Med 57:2593198. https:\/\/doi.org\/10.1080\/07853890.2025.2593198","journal-title":"Ann Med"},{"key":"4366_CR30","doi-asserted-by":"publisher","first-page":"3347","DOI":"10.32604\/or.2025.067445","volume":"33","author":"J Lei","year":"2025","unstructured":"Lei J, Ni Z, Zhang R (2025) Universal CAR-T cell therapy for cancer treatment: advances and challenges. Oncol Res 33:3347\u20133373. https:\/\/doi.org\/10.32604\/or.2025.067445","journal-title":"Oncol Res"},{"key":"4366_CR31","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1007\/s00262-018-2154-8","volume":"67","author":"J Arranz-Nicolas","year":"2018","unstructured":"Arranz-Nicolas J et al (2018) Diacylglycerol kinase alpha inactivation is an integral component of the costimulatory pathway that amplifies TCR signals. Cancer Immunol Immunother 67:965\u2013980. https:\/\/doi.org\/10.1007\/s00262-018-2154-8","journal-title":"Cancer Immunol Immunother"},{"key":"4366_CR32","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20231486","author":"N Miao","year":"2024","unstructured":"Miao N et al (2024) Tumor cell-intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance. J Exp Med. https:\/\/doi.org\/10.1084\/jem.20231486","journal-title":"J Exp Med"},{"key":"4366_CR33","doi-asserted-by":"publisher","first-page":"1663","DOI":"10.1194\/jlr.M900058-JLR200","volume":"50","author":"HA Hostetler","year":"2009","unstructured":"Hostetler HA et al (2009) L-FABP directly interacts with PPARalpha in cultured primary hepatocytes. J Lipid Res 50:1663\u20131675. https:\/\/doi.org\/10.1194\/jlr.M900058-JLR200","journal-title":"J Lipid Res"},{"key":"4366_CR34","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1158\/2326-6066.CIR-18-0095","volume":"6","author":"PS Chowdhury","year":"2018","unstructured":"Chowdhury PS, Chamoto K, Kumar A, Honjo T (2018) PPAR-induced fatty acid oxidation in t cells increases the number of tumor-reactive CD8(+) t cells and facilitates anti-PD-1 therapy. Cancer Immunol Res 6:1375\u20131387. https:\/\/doi.org\/10.1158\/2326-6066.CIR-18-0095","journal-title":"Cancer Immunol Res"},{"key":"4366_CR35","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aay9283","author":"H Frizzell","year":"2020","unstructured":"Frizzell H et al (2020) Organ-specific isoform selection of fatty acid-binding proteins in tissue-resident lymphocytes. Sci Immunol. https:\/\/doi.org\/10.1126\/sciimmunol.aay9283","journal-title":"Sci Immunol"},{"key":"4366_CR36","doi-asserted-by":"publisher","first-page":"14135","DOI":"10.1021\/acs.est.4c03344","volume":"58","author":"S Wang","year":"2024","unstructured":"Wang S, Zhang Z, Saunders LJ, Li D, Li L (2024) Understanding the impacts of presystemic metabolism on the human oral bioavailability of chemicals. Environ Sci Technol 58:14135\u201314145. https:\/\/doi.org\/10.1021\/acs.est.4c03344","journal-title":"Environ Sci Technol"},{"key":"4366_CR37","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1038\/s41420-025-02516-7","volume":"11","author":"N Miao","year":"2025","unstructured":"Miao N et al (2025) Mitochondrial reactive oxygen species promote cancer metastasis and tumor microenvironment immunosuppression through gasdermin D. Cell Death Discov 11:219. https:\/\/doi.org\/10.1038\/s41420-025-02516-7","journal-title":"Cell Death Discov"},{"key":"4366_CR38","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00823-w","volume":"6","author":"K Shah","year":"2021","unstructured":"Shah K, Al-Haidari A, Sun J, Kazi JU (2021) T cell receptor (TCR) signaling in health and disease. Signal Transduct Target Ther 6:412. https:\/\/doi.org\/10.1038\/s41392-021-00823-w","journal-title":"Signal Transduct Target Ther"}],"container-title":["Cancer Immunology, Immunotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-026-04366-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00262-026-04366-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-026-04366-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T11:55:00Z","timestamp":1775130900000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00262-026-04366-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,2]]},"references-count":38,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["4366"],"URL":"https:\/\/doi.org\/10.1007\/s00262-026-04366-3","relation":{},"ISSN":["1432-0851"],"issn-type":[{"value":"1432-0851","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,2]]},"assertion":[{"value":"25 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All animal experiments were approved by the Institutional Animal Care and Use Committee of Naval Medical University. Tumor measurements\/volumes were in accordance with the IACUC guidelines.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent for participate"}},{"value":"All authors have approved the content of this manuscript and provided consent for publication.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"134"}}