{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T19:25:30Z","timestamp":1787167530844,"version":"build-2736575974"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T00:00:00Z","timestamp":1707782400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T00:00:00Z","timestamp":1707782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100012459","name":"Chongqing Graduate Student Research Innovation Project","doi-asserted-by":"publisher","award":["CYS20214"],"award-info":[{"award-number":["CYS20214"]}],"id":[{"id":"10.13039\/501100012459","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012459","name":"Chongqing Graduate Student Research Innovation Project","doi-asserted-by":"publisher","award":["CYS20214"],"award-info":[{"award-number":["CYS20214"]}],"id":[{"id":"10.13039\/501100012459","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Program for Youth Innovation in Future Medicine, Chongqing Medical University","award":["W0155"],"award-info":[{"award-number":["W0155"]}]},{"name":"Program for Youth Innovation in Future Medicine, Chongqing Medical University","award":["W0155"],"award-info":[{"award-number":["W0155"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Immunol Immunother"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Tumor immunotherapy is booming around the world. However, strategies to activate the immune system and alleviate the immunosuppression still need to be refined. Here, we demonstrate for the first time that low-intensity pulsed ultrasound (LIPUS, spatial average time average intensity (\n                    <jats:italic>I<\/jats:italic>\n                    <jats:sub>sata<\/jats:sub>\n                    ) is 200 mW\/cm\n                    <jats:sup>2<\/jats:sup>\n                    , frequency is 0.3\u00a0MHz, repetition frequency is 1\u00a0kHz, and duty cycle is 20%) triggers the immune system and further reverses the immunosuppressive state in the mouse models of breast cancer by irradiating the spleen of mice. LIPUS inhibited tumor growth and extended survival in mice with 4\u00a0T-1 tumors. Further studies had previously shown that LIPUS enhanced the activation of CD4\n                    <jats:sup>+<\/jats:sup>\n                    and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in the spleen and led to significant changes in cytokines, as well as induced upregulation of mRNA levels involved in multiple immune regulatory pathways in the spleen. In addition, LIPUS promoted tumor-infiltrating lymphocyte accumulation and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell activation and improved the dynamics of cytokines\/chemokines in the tumor microenvironment, resulting in a reversal of the immunosuppressive state of the tumor microenvironment. These results suggest a novel approach to activate the immune response by irradiating the spleen with LIPUS.\n                  <\/jats:p>","DOI":"10.1007\/s00262-023-03613-1","type":"journal-article","created":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T07:02:29Z","timestamp":1707807749000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Low-intensity pulsed ultrasound activated the anti-tumor immunity by irradiating the spleen of mice in 4\u00a0T-1 breast cancer"],"prefix":"10.1007","volume":"73","author":[{"given":"Yi","family":"Xia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijie","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinfang","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haopeng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilin","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,13]]},"reference":[{"issue":"3","key":"3613_CR1","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1038\/s41573-018-0006-z","volume":"18","author":"RS Riley","year":"2019","unstructured":"Riley RS, June CH, Langer R, Mitchell MJ (2019) Delivery technologies for cancer immunotherapy. Nat Rev Drug Discov 18(3):175\u2013196","journal-title":"Nat Rev Drug Discov"},{"issue":"4","key":"3613_CR2","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/nrc3239","volume":"12","author":"DM Pardoll","year":"2012","unstructured":"Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252\u2013264","journal-title":"Nat Rev Cancer"},{"issue":"1","key":"3613_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.immuni.2013.07.012","volume":"39","author":"DS Chen","year":"2013","unstructured":"Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39(1):1\u201310","journal-title":"Immunity"},{"issue":"15","key":"3613_CR4","doi-asserted-by":"publisher","first-page":"3608","DOI":"10.7150\/thno.21225","volume":"7","author":"CT Curley","year":"2017","unstructured":"Curley CT, Sheybani ND, Bullock TN, Price RJ (2017) Focused ultrasound immunotherapy for central nervous system pathologies: challenges and opportunities. Theranostics 7(15):3608\u20133623","journal-title":"Theranostics"},{"issue":"1","key":"3613_CR5","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1186\/s40425-019-0787-6","volume":"7","author":"H Westdorp","year":"2019","unstructured":"Westdorp H, Creemers JHA, van Oort IM, Schreibelt G, Gorris MAJ, Mehra N, Simons M, de Goede AL, van Rossum MM, Croockewit AJ, Figdor CG, Witjes JA, Aarntzen EHJG, Mus RDM, Br\u00fcning M, Petry K, Gotthardt M, Barentsz JO, de Vries IJM, Gerritsen WR (2019) Blood-derived dendritic cell vaccinations induce immune responses that correlate with clinical outcome in patients with chemo-naive castration-resistant prostate cancer. J Immunother Cancer 7(1):302","journal-title":"J Immunother Cancer"},{"issue":"4","key":"3613_CR6","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1038\/nrd.2015.35","volume":"15","author":"A Hoos","year":"2016","unstructured":"Hoos A (2016) Development of immuno-oncology drugs\u2013from CTLA4 to PD1 to the next generations. Nat Rev Drug Discov 15(4):235\u2013247","journal-title":"Nat Rev Drug Discov"},{"issue":"10","key":"3613_CR7","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1038\/nrclinonc.2011.116","volume":"8","author":"SA Rosenberg","year":"2011","unstructured":"Rosenberg SA (2011) Cell transfer immunotherapy for metastatic solid cancer\u2013what clinicians need to know. Nat Rev Clin Oncol 8(10):577\u2013585","journal-title":"Nat Rev Clin Oncol"},{"issue":"7","key":"3613_CR8","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1016\/j.jtho.2016.02.015","volume":"11","author":"T Shukuya","year":"2016","unstructured":"Shukuya T, Carbone DP (2016) Predictive markers for the efficacy of anti-PD-1\/PD-L1 antibodies in lung cancer. J Thorac Oncol 11(7):976\u2013988","journal-title":"J Thorac Oncol"},{"issue":"2","key":"3613_CR9","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1056\/NEJMoa1504627","volume":"373","author":"J Brahmer","year":"2015","unstructured":"Brahmer J, Reckamp KL, Baas P, Crin\u00f2 L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Ar\u00e9n Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373(2):123\u2013135","journal-title":"N Engl J Med"},{"issue":"7","key":"3613_CR10","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1007\/s00262-013-1434-6","volume":"62","author":"JC Becker","year":"2013","unstructured":"Becker JC, Andersen MH, Schrama D, Thor Straten P (2013) Immune-suppressive properties of the tumor microenvironment. Cancer Immunol Immunother 62(7):1137\u20131148","journal-title":"Cancer Immunol Immunother"},{"issue":"11","key":"3613_CR11","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1038\/nm.3394","volume":"19","author":"DF Quail","year":"2013","unstructured":"Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19(11):1423\u20131437","journal-title":"Nat Med"},{"key":"3613_CR12","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1146\/annurev.immunol.25.022106.141609","volume":"25","author":"GA Rabinovich","year":"2007","unstructured":"Rabinovich GA, Gabrilovich D, Sotomayor EM (2007) Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 25:267\u2013296","journal-title":"Annu Rev Immunol"},{"issue":"8","key":"3613_CR13","doi-asserted-by":"publisher","first-page":"1482","DOI":"10.1093\/annonc\/mdw168","volume":"27","author":"JM Pitt","year":"2016","unstructured":"Pitt JM, Marabelle A, Eggermont A, Soria JC, Kroemer G, Zitvogel L (2016) Targeting the tumor microenvironment: removing obstruction to anticancer immune responses and immunotherapy. Ann Oncol 27(8):1482\u20131492","journal-title":"Ann Oncol"},{"issue":"5","key":"3613_CR14","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","volume":"144","author":"D Hanahan","year":"2011","unstructured":"Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646\u2013674","journal-title":"Cell"},{"issue":"1","key":"3613_CR15","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1038\/s41467-019-08721-0","volume":"10","author":"DP Zachs","year":"2019","unstructured":"Zachs DP, Offutt SJ, Graham RS, Kim Y, Mueller J, Auger JL, Schuldt NJ, Kaiser CRW, Heiller AP, Dutta R, Guo H, Alford JK, Binstadt BA, Lim HH (2019) Noninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis. Nat Commun 10(1):951","journal-title":"Nat Commun"},{"issue":"10","key":"3613_CR16","doi-asserted-by":"publisher","first-page":"2721","DOI":"10.1002\/jum.14979","volume":"38","author":"B Liu","year":"2019","unstructured":"Liu B, Zhou W, Wu J, Chen W, Chen J, Wang Y (2019) Low-intensity pulsed ultrasound relieves mild and severe myelosuppression induced by cyclophosphamide in rabbits. J Ultrasound Med 38(10):2721\u20132731","journal-title":"J Ultrasound Med"},{"issue":"9","key":"3613_CR17","doi-asserted-by":"publisher","first-page":"BSR20201350","DOI":"10.1042\/BSR20201350","volume":"40","author":"W Wang","year":"2020","unstructured":"Wang W, Luo D, Chen J, Chen J, Xia Y, Chen W, Wang Y (2020) Amelioration of cyclophosphamide-induced myelosuppression during treatment to rats with breast cancer through low-intensity pulsed ultrasound. Biosci Rep 40(9):BSR20201350","journal-title":"Biosci Rep"},{"issue":"7","key":"3613_CR18","doi-asserted-by":"publisher","first-page":"1602","DOI":"10.1016\/j.ultrasmedbio.2023.03.008","volume":"49","author":"W Tang","year":"2023","unstructured":"Tang W, Xia Y, Deng J, Xu H, Tang Y, Xiao X, Wu L, Song G, Qin J, Wang Y (2023) Anti-inflammatory effect of low-Intensity ultrasound in septic rats. Ultrasound Med Biol 49(7):1602\u20131610","journal-title":"Ultrasound Med Biol"},{"issue":"33","key":"3613_CR19","doi-asserted-by":"publisher","first-page":"eaau6085","DOI":"10.1126\/sciimmunol.aau6085","volume":"4","author":"SM Lewis","year":"2019","unstructured":"Lewis SM, Williams A, Eisenbarth SC (2019) Structure and function of the immune system in the spleen. Sci Immunol 4(33):eaau6085","journal-title":"Sci Immunol"},{"key":"3613_CR20","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1016\/j.ijbiomac.2015.06.052","volume":"80","author":"K Zhong","year":"2015","unstructured":"Zhong K, Tong L, Liu L, Zhou X, Liu X, Zhang Q, Zhou S (2015) Immunoregulatory and antitumor activity of schizophyllan under ultrasonic treatment. Int J Biol Macromol 80:302\u2013308","journal-title":"Int J Biol Macromol"},{"issue":"12","key":"3613_CR21","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1084\/jem.20020066","volume":"195","author":"JT Tan","year":"2002","unstructured":"Tan JT, Ernst B, Kieper WC, LeRoy E, Sprent J, Surh CD (2002) Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J Exp Med 195(12):1523\u20131532","journal-title":"J Exp Med"},{"issue":"6","key":"3613_CR22","volume":"9","author":"J Chen","year":"2022","unstructured":"Chen J, Wang W, Li C, Xia Y, Xu H, Chen J, Chen W, Wang Y (2022) Potential application of low-intensity pulsed ultrasound in delaying aging for mice. Gerontology 9(6):e002157","journal-title":"Gerontology"},{"issue":"2","key":"3613_CR23","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1158\/2326-6066.CIR-13-0216","volume":"2","author":"HJ Kim","year":"2014","unstructured":"Kim HJ, Cantor H (2014) CD4 T-cell subsets and tumor immunity: the helpful and the not-so-helpful. Cancer Immunol Res 2(2):91\u201398","journal-title":"Cancer Immunol Res"},{"issue":"9","key":"3613_CR24","doi-asserted-by":"publisher","first-page":"2162","DOI":"10.1158\/0008-5472.CAN-11-3687","volume":"72","author":"A Facciabene","year":"2012","unstructured":"Facciabene A, Motz GT, Coukos G (2012) T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res 72(9):2162\u20132171","journal-title":"Cancer Res"},{"issue":"6","key":"3613_CR25","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-002157","volume":"9","author":"J Niogret","year":"2021","unstructured":"Niogret J, Berger H, Rebe C, Mary R, Ballot E, Truntzer C, Thibaudin M, Derang\u00e8re V, Hibos C, Hampe L, Rageot D, Accogli T, Joubert P, Routy B, Harker J, Vegran F, Ghiringhelli F, Chalmin F (2021) Follicular helper-T cells restore CD8+-dependent antitumor immunity and anti-PD-L1\/PD-1 efficacy. J Immunother Cancer 9(6):e002157","journal-title":"J Immunother Cancer"},{"issue":"9","key":"3613_CR26","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1007\/s00011-013-0645-9","volume":"62","author":"B Lakshmi Narendra","year":"2013","unstructured":"Lakshmi Narendra B, Eshvendar Reddy K, Shantikumar S, Ramakrishna S (2013) Immune system: a double-edged sword in cancer. Inflamm Res 62(9):823\u2013834","journal-title":"Inflamm Res"},{"issue":"23","key":"3613_CR27","doi-asserted-by":"publisher","first-page":"6703","DOI":"10.1039\/D0BM00804D","volume":"8","author":"M Tan","year":"2020","unstructured":"Tan M, Chen Y, Guo Y, Yang C, Liu M, Guo D, Wang Z, Cao Y, Ran H (2020) A low-intensity focused ultrasound-assisted nanocomposite for advanced triple cancer therapy: local chemotherapy, therapeutic extracellular vesicles and combined immunotherapy. Biomater Sci 8(23):6703\u20136717","journal-title":"Biomater Sci"},{"key":"3613_CR28","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.106655","volume":"85","author":"KE Cole","year":"2020","unstructured":"Cole KE, Ly QP, Hollingsworth MA, Cox JL, Stromnes IM, Padussis JC, Foster JM, Vargas LM, Talmadge JE (2020) Comparative phenotypes of peripheral blood and spleen cells from cancer patients. Int Immunopharmacol 85:106655","journal-title":"Int Immunopharmacol"},{"issue":"1","key":"3613_CR29","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1111\/j.1365-2249.2008.03734.x","volume":"154","author":"MM Vel\u00e1squez-Lopera","year":"2008","unstructured":"Vel\u00e1squez-Lopera MM, Correa LA, Garc\u00eda LF (2008) Human spleen contains different subsets of dendritic cells and regulatory T lymphocytes. Clin Exp Immunol 154(1):107\u2013114","journal-title":"Clin Exp Immunol"},{"issue":"1","key":"3613_CR30","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1111\/imr.12742","volume":"289","author":"JR Groom","year":"2019","unstructured":"Groom JR (2019) Regulators of T-cell fate: Integration of cell migration, differentiation and function. Immunol Rev 289(1):101\u2013114","journal-title":"Immunol Rev"},{"issue":"6","key":"3613_CR31","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1016\/j.immuni.2019.05.013","volume":"50","author":"E Humblin","year":"2019","unstructured":"Humblin E, Kamphorst AO (2019) CXCR3-CXCL9: it\u2019s all in the tumor. Immunity 50(6):1347\u20131349","journal-title":"Immunity"},{"key":"3613_CR32","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.ctrv.2017.11.007","volume":"63","author":"R Tokunaga","year":"2018","unstructured":"Tokunaga R, Zhang W, Naseem M, Puccini A, Berger MD, Soni S, McSkane M, Baba H, Lenz HJ (2018) CXCL9, CXCL10, CXCL11\/CXCR3 axis for immune activation-A target for novel cancer therapy. Cancer Treat Rev 63:40\u201347","journal-title":"Cancer Treat Rev"},{"issue":"2","key":"3613_CR33","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.canlet.2015.07.009","volume":"367","author":"MH Mannino","year":"2015","unstructured":"Mannino MH, Zhu Z, Xiao H, Bai Q, Wakefield MR, Fang Y (2015) The paradoxical role of IL-10 in immunity and cancer. Cancer Lett 367(2):103\u2013107","journal-title":"Cancer Lett"},{"issue":"1","key":"3613_CR34","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1038\/s41467-019-08538-x","volume":"10","author":"X Yu","year":"2019","unstructured":"Yu X, Chen L, Liu J, Dai B, Xu G, Shen G, Luo Q, Zhang Z (2019) Immune modulation of liver sinusoidal endothelial cells by melittin nanoparticles suppresses liver metastasis. Nat Commun 10(1):574","journal-title":"Nat Commun"}],"container-title":["Cancer Immunology, Immunotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-023-03613-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00262-023-03613-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-023-03613-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,12]],"date-time":"2024-03-12T06:01:52Z","timestamp":1710223312000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00262-023-03613-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,13]]},"references-count":34,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["3613"],"URL":"https:\/\/doi.org\/10.1007\/s00262-023-03613-1","relation":{},"ISSN":["1432-0851"],"issn-type":[{"value":"1432-0851","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,13]]},"assertion":[{"value":"18 May 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 November 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 February 2024","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 that they have no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All of the authors consent for publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"All animal studies were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and approved by the Ethics Committee of Chongqing Medical University (reference number 2022098).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}}],"article-number":"50"}}