{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T02:40:43Z","timestamp":1788489643773,"version":"build-2803163510"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP22K08712"],"award-info":[{"award-number":["JP22K08712"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012330","name":"Okayama University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100012330","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Immunol Immunother"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Recent studies have revealed that CD8<jats:sup>+<\/jats:sup> T cells can be activated via genetic upregulation of HIF-1\u03b1, thereby augmenting antitumor effector functions. HIF-1\u03b1 upregulation can be attained by inhibiting HIF-prolyl hydroxylase (HIF-PH) under normoxic conditions, termed pseudohypoxia. This study investigated whether pseudohypoxia induced by HIF-PH inhibitors suppresses Microsatellite stable (MSS) colorectal cancer (CRC) by affecting tumor immune response.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>The HIF-PH inhibitors Roxadustat and Vadadustat were utilized in this study. In vitro, we assessed the effects of HIF-PH inhibitors on human and murine colon cancer cell lines (SW480, HT29, Colon26) and murine T cells. In vivo experiments were performed with mice bearing Colon26 tumors to evaluate the effect of these inhibitors on tumor immune responses. Tumor and spleen samples were analyzed using immunohistochemistry, RT-qPCR, and flow cytometry to elucidate potential mechanisms.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>HIF-PH inhibitors demonstrated antitumor effects in vivo but not in vitro. These inhibitors enhanced the tumor immune response by increasing the infiltration of CD8<jats:sup>+<\/jats:sup> and CD4<jats:sup>+<\/jats:sup> tumor-infiltrating lymphocytes (TILs). HIF-PH inhibitors induced IL-2 production in splenic and intratumoral CD4<jats:sup>+<\/jats:sup> T cells, promoting T cell proliferation, differentiation, and immune responses. Roxadustat synergistically enhanced the efficacy of anti-PD-1 antibody for MSS cancer by increasing the recruitment of TILs and augmenting effector-like CD8<jats:sup>+<\/jats:sup> T cells.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Pseudohypoxia induced by HIF-PH inhibitors activates antitumor immune responses, at least in part, through the induction of IL-2 secretion from CD4<jats:sup>+<\/jats:sup> T cells in the spleen and tumor microenvironment, thereby enhancing immune efficacy against MSS CRC.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s00262-025-04067-3","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T14:28:15Z","timestamp":1746800895000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["HIF-PH inhibitors induce pseudohypoxia in T cells and suppress the growth of microsatellite stable colorectal cancer by enhancing antitumor immune responses"],"prefix":"10.1007","volume":"74","author":[{"given":"Yuehua","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiaki","family":"Ohara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Hamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuze","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Noma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Tazawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayoshi","family":"Fujisawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teizo","family":"Yoshimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Matsukawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,9]]},"reference":[{"key":"4067_CR1","doi-asserted-by":"publisher","first-page":"1208140","DOI":"10.3389\/fonc.2023.1208140","volume":"13","author":"S Tirendi","year":"2023","unstructured":"Tirendi S, Marengo B, Domenicotti C, Bassi AM, Almonti V, Vernazza S (2023) Colorectal cancer and therapy response: a focus on the main mechanisms involved. Front Oncol 13:1208140","journal-title":"Front Oncol"},{"issue":"11","key":"4067_CR2","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1093\/jnci\/djz093","volume":"111","author":"AJ Franke","year":"2019","unstructured":"Franke AJ, Skelton WP, Starr JS, Parekh H, Lee JJ, Overman MJ, Allegra C, George TJ (2019) Immunotherapy for colorectal cancer: a review of current and novel therapeutic approaches. J Natl Cancer Inst 111(11):1131\u20131141","journal-title":"J Natl Cancer Inst"},{"issue":"2","key":"4067_CR3","doi-asserted-by":"publisher","first-page":"258","DOI":"10.3390\/cells12020258","volume":"12","author":"I Yu","year":"2023","unstructured":"Yu I, Dakwar A, Takabe K (2023) Immunotherapy: recent advances and its future as a neoadjuvant, adjuvant, and primary treatment in colorectal cancer. Cells 12(2):258","journal-title":"Cells"},{"issue":"10","key":"4067_CR4","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.3748\/wjg.v11.i10.1535","volume":"11","author":"T Okuda","year":"2005","unstructured":"Okuda T, Azuma T, Ohtani M, Masaki R, Ito Y, Yamazaki Y, Ito S, Kuriyama M (2005) Hypoxia-inducible factor 1 alpha and vascular endothelial growth factor overexpression in ischemic colitis. World J Gastroenterol 11(10):1535\u20131539","journal-title":"World J Gastroenterol"},{"key":"4067_CR5","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.114646","volume":"162","author":"K Mortezaee","year":"2023","unstructured":"Mortezaee K, Majidpoor J, Kharazinejad E (2023) The impact of hypoxia on tumor-mediated bypassing anti-PD-(L)1 therapy. Biomed Pharmacother 162:114646","journal-title":"Biomed Pharmacother"},{"issue":"11","key":"4067_CR6","doi-asserted-by":"publisher","first-page":"2547","DOI":"10.1016\/j.celrep.2017.08.071","volume":"20","author":"Y Gropper","year":"2017","unstructured":"Gropper Y, Feferman T, Shalit T, Salame TM, Porat Z, Shakhar G (2017) Culturing CTLs under hypoxic conditions enhances their cytolysis and improves their anti-tumor function. Cell Rep 20(11):2547\u20132555","journal-title":"Cell Rep"},{"key":"4067_CR7","doi-asserted-by":"crossref","unstructured":"Liikanen I, Lauhan C, Quon S, Omilusik K, Phan AT, Bartroli LB, Ferry A, Goulding J, Chen J, Scott-Browne JP, Yustein JT, Scharping NE, Witherden DA, Goldrath AW (2021) Hypoxia-inducible factor activity promotes antitumor effector function and tissue residency by CD8+ T cells. J Clin Invest. 131(7)","DOI":"10.1172\/JCI143729"},{"issue":"3","key":"4067_CR8","doi-asserted-by":"publisher","first-page":"3037","DOI":"10.3390\/ijms24033037","volume":"24","author":"C Ogawa","year":"2023","unstructured":"Ogawa C, Tsuchiya K, Maeda K (2023) Hypoxia-inducible factor prolyl hydroxylase inhibitors and iron metabolism. Int J Mol Sci 24(3):3037","journal-title":"Int J Mol Sci"},{"issue":"21","key":"4067_CR9","doi-asserted-by":"publisher","first-page":"4368","DOI":"10.1200\/JCO.2002.10.088","volume":"20","author":"HF Dvorak","year":"2002","unstructured":"Dvorak HF (2002) Vascular permeability factor\/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 20(21):4368\u20134380","journal-title":"J Clin Oncol"},{"issue":"4","key":"4067_CR10","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1093\/ndt\/gfab349","volume":"37","author":"J Barratt","year":"2022","unstructured":"Barratt J, Andric B, Tataradze A, Schomig M, Reusch M, Valluri U, Mariat C (2022) Erratum to: Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a phase 3, randomised, open-label, active-controlled study (DOLOMITES). Nephrol Dial Transplant 37(4):805","journal-title":"Nephrol Dial Transplant"},{"issue":"11","key":"4067_CR11","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1056\/NEJMoa1813599","volume":"381","author":"N Chen","year":"2019","unstructured":"Chen N, Hao C, Peng X, Lin H, Yin A, Hao L, Tao Y, Liang X, Liu Z, Xing C, Chen J, Luo L, Zuo L, Liao Y, Liu BC, Leong R, Wang C, Liu C, Neff T, Szczech L, Yu KP (2019) Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med 381(11):1001\u20131010","journal-title":"N Engl J Med"},{"issue":"1","key":"4067_CR12","first-page":"13","volume":"14","author":"JM Carethers","year":"2000","unstructured":"Carethers JM, Pham TT (2000) Mutations of transforming growth factor beta 1 type II receptor, BAX, and insulin-like growth factor II receptor genes in microsatellite unstable cell lines. In Vivo 14(1):13\u201320","journal-title":"In Vivo"},{"issue":"1","key":"4067_CR13","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1186\/s12885-021-08974-3","volume":"21","author":"Y Sato","year":"2021","unstructured":"Sato Y, Fu Y, Liu H, Lee MY, Shaw MH (2021) Tumor-immune profiling of CT-26 and Colon 26 syngeneic mouse models reveals mechanism of anti-PD-1 response. BMC Cancer 21(1):1222","journal-title":"BMC Cancer"},{"key":"4067_CR14","doi-asserted-by":"publisher","first-page":"1007579","DOI":"10.3389\/fimmu.2022.1007579","volume":"13","author":"J Chen","year":"2022","unstructured":"Chen J, Liao S, Xiao Z, Pan Q, Wang X, Shen K, Wang S, Yang L, Guo F, Liu HF, Pan Q (2022) The development and improvement of immunodeficient mice and humanized immune system mouse models. Front Immunol 13:1007579","journal-title":"Front Immunol"},{"issue":"5","key":"4067_CR15","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1016\/j.cell.2011.07.033","volume":"146","author":"EV Dang","year":"2011","unstructured":"Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR, Luo W, Zeller K, Shimoda L, Topalian SL, Semenza GL, Dang CV, Pardoll DM, Pan F (2011) Control of T(H)17\/T(reg) balance by hypoxia-inducible factor 1. Cell 146(5):772\u2013784","journal-title":"Cell"},{"issue":"15","key":"4067_CR16","doi-asserted-by":"publisher","first-page":"2629","DOI":"10.3390\/cancers16152629","volume":"16","author":"N Munoz Perez","year":"2024","unstructured":"Munoz Perez N, Pensabene JM, Galbo PM Jr, Sadeghipour N, Xiu J, Moziak K, Yazejian RM, Welch RL, Bell WR, Sengupta S, Aulakh S, Eberhart CG, Loeb DM, Eskandar E, Zheng D, Zang X, Martin AM (2024) VISTA emerges as a promising target against immune evasion mechanisms in medulloblastoma. Cancers (Basel). 16(15):2629","journal-title":"Cancers (Basel)."},{"issue":"3","key":"4067_CR17","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1016\/j.immuni.2015.08.006","volume":"43","author":"NS Joshi","year":"2015","unstructured":"Joshi NS, Akama-Garren EH, Lu Y, Lee DY, Chang GP, Li A, DuPage M, Tammela T, Kerper NR, Farago AF, Robbins R, Crowley DM, Bronson RT, Jacks T (2015) Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor T cell responses. Immunity 43(3):579\u2013590","journal-title":"Immunity"},{"issue":"3","key":"4067_CR18","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1038\/nri3156","volume":"12","author":"O Boyman","year":"2012","unstructured":"Boyman O, Sprent J (2012) The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol 12(3):180\u2013190","journal-title":"Nat Rev Immunol"},{"issue":"68","key":"4067_CR19","doi-asserted-by":"publisher","first-page":"eabl6322","DOI":"10.1126\/sciimmunol.abl6322","volume":"7","author":"SM Kahan","year":"2022","unstructured":"Kahan SM, Bakshi RK, Ingram JT, Hendrickson RC, Lefkowitz EJ, Crossman DK, Harrington LE, Weaver CT, Zajac AJ (2022) Intrinsic IL-2 production by effector CD8 T cells affects IL-2 signaling and promotes fate decisions, stemness, and protection. Sci Immunol. 7(68):eabl6322","journal-title":"Sci Immunol."},{"issue":"5","key":"4067_CR20","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1016\/j.immuni.2020.04.014","volume":"52","author":"JC Beltra","year":"2020","unstructured":"Beltra JC, Manne S, Abdel-Hakeem MS, Kurachi M, Giles JR, Chen Z, Casella V, Ngiow SF, Khan O, Huang YJ, Yan P, Nzingha K, Xu W, Amaravadi RK, Xu X, Karakousis GC, Mitchell TC, Schuchter LM, Huang AC, Wherry EJ (2020) Developmental relationships of four exhausted CD8(+) T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity 52(5):825\u2013841828","journal-title":"Immunity"},{"key":"4067_CR21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.715234","volume":"12","author":"JS Dolina","year":"2021","unstructured":"Dolina JS, Van Braeckel-Budimir N, Thomas GD, Salek-Ardakani S (2021) CD8(+) T cell exhaustion in cancer. Front Immunol 12:715234","journal-title":"Front Immunol"},{"issue":"22","key":"4067_CR22","doi-asserted-by":"publisher","first-page":"5775","DOI":"10.1158\/1078-0432.CCR-20-2901","volume":"26","author":"M Nusrat","year":"2020","unstructured":"Nusrat M (2020) Response to anti-PD-1 in microsatellite-stable colorectal cancer: a STAT need. Clin Cancer Res 26(22):5775\u20135777","journal-title":"Clin Cancer Res"},{"issue":"26","key":"4067_CR23","doi-asserted-by":"publisher","first-page":"2509","DOI":"10.1056\/NEJMoa1500596","volume":"372","author":"DT Le","year":"2015","unstructured":"Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26):2509\u20132520","journal-title":"N Engl J Med"},{"issue":"3","key":"4067_CR24","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1038\/s41590-019-0312-6","volume":"20","author":"BC Miller","year":"2019","unstructured":"Miller BC, Sen DR, Al Abosy R, Bi K, Virkud YV, LaFleur MW, Yates KB, Lako A, Felt K, Naik GS, Manos M, Gjini E, Kuchroo JR, Ishizuka JJ, Collier JL, Griffin GK, Maleri S, Comstock DE, Weiss SA, Brown FD, Panda A, Zimmer MD, Manguso RT, Hodi FS, Rodig SJ, Sharpe AH, Haining WN (2019) Subsets of exhausted CD8(+) T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol 20(3):326\u2013336","journal-title":"Nat Immunol"},{"issue":"3","key":"4067_CR25","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2021.101017","volume":"14","author":"VL Codony","year":"2021","unstructured":"Codony VL, Tavassoli M (2021) Hypoxia-induced therapy resistance: Available hypoxia-targeting strategies and current advances in head and neck cancer. Transl Oncol 14(3):101017","journal-title":"Transl Oncol"},{"key":"4067_CR26","doi-asserted-by":"publisher","first-page":"1293723","DOI":"10.3389\/fimmu.2024.1293723","volume":"15","author":"D Bargiela","year":"2024","unstructured":"Bargiela D, Cunha PP, Velica P, Krause LCM, Brice M, Barbieri L, Gojkovic M, Foskolou IP, Rundqvist H, Johnson RS (2024) The factor inhibiting HIF regulates T cell differentiation and anti-tumour efficacy. Front Immunol 15:1293723","journal-title":"Front Immunol"},{"issue":"5516","key":"4067_CR27","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1126\/science.1059796","volume":"292","author":"P Jaakkola","year":"2001","unstructured":"Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292(5516):468\u2013472","journal-title":"Science"},{"issue":"20","key":"4067_CR28","doi-asserted-by":"publisher","first-page":"e167396","DOI":"10.1172\/jci.insight.167394","volume":"8","author":"A Garcia-Del Rio","year":"2023","unstructured":"Garcia-Del Rio A, Prieto-Fernandez E, Egia-Mendikute L, Antonana-Vildosola A, Jimenez-Lasheras B, Lee SY, Barreira-Manrique A, Zanetti SR, de Blas A, Velasco-Beltran P, Bosch A, Aransay AM, Palazon A (2023) Factor-inhibiting HIF (FIH) promotes lung cancer progression. JCI Insight. 8(20):e167396","journal-title":"JCI Insight."},{"issue":"5","key":"4067_CR29","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1016\/j.ccell.2017.10.003","volume":"32","author":"A Palazon","year":"2017","unstructured":"Palazon A, Tyrakis PA, Macias D, Velica P, Rundqvist H, Fitzpatrick S, Vojnovic N, Phan AT, Loman N, Hedenfalk I, Hatschek T, Lovrot J, Foukakis T, Goldrath AW, Bergh J, Johnson RS (2017) An HIF-1alpha\/VEGF-A axis in cytotoxic t cells regulates tumor progression. Cancer Cell 32(5):669-683e665","journal-title":"Cancer Cell"},{"issue":"47","key":"4067_CR30","doi-asserted-by":"publisher","first-page":"17071","DOI":"10.1073\/pnas.0506070102","volume":"102","author":"AK Neumann","year":"2005","unstructured":"Neumann AK, Yang J, Biju MP, Joseph SK, Johnson RS, Haase VH, Freedman BD, Turka LA (2005) Hypoxia inducible factor 1 alpha regulates T cell receptor signal transduction. Proc Natl Acad Sci U S A 102(47):17071\u201317076","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"12","key":"4067_CR31","doi-asserted-by":"publisher","first-page":"5451","DOI":"10.4049\/jimmunol.1490019","volume":"192","author":"SA Rosenberg","year":"2014","unstructured":"Rosenberg SA (2014) IL-2: the first effective immunotherapy for human cancer. J Immunol 192(12):5451\u20135458","journal-title":"J Immunol"},{"issue":"2","key":"4067_CR32","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/j.cyto.2014.11.024","volume":"71","author":"MY Balkhi","year":"2015","unstructured":"Balkhi MY, Ma Q, Ahmad S, Junghans RP (2015) T cell exhaustion and Interleukin 2 downregulation. Cytokine 71(2):339\u2013347","journal-title":"Cytokine"},{"issue":"25","key":"4067_CR33","doi-asserted-by":"publisher","first-page":"eaat1482","DOI":"10.1126\/sciimmunol.aat1482","volume":"3","author":"AK Abbas","year":"2018","unstructured":"Abbas AK, Trotta E, Simeonov DR, Marson A, Bluestone JA (2018) Revisiting IL-2: biology and therapeutic prospects. Sci Immunol. 3(25):eaat1482","journal-title":"Sci Immunol."},{"key":"4067_CR34","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.3389\/fimmu.2020.01106","volume":"11","author":"A Ghelani","year":"2020","unstructured":"Ghelani A, Bates D, Conner K, Wu MZ, Lu J, Hu YL, Li CM, Chaudhry A, Sohn SJ (2020) Defining the threshold IL-2 signal required for induction of selective treg cell responses using engineered IL-2 muteins. Front Immunol 11:1106","journal-title":"Front Immunol"},{"issue":"10","key":"4067_CR35","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1038\/s41577-022-00680-w","volume":"22","author":"R Hernandez","year":"2022","unstructured":"Hernandez R, Poder J, LaPorte KM, Malek TR (2022) Engineering IL-2 for immunotherapy of autoimmunity and cancer. Nat Rev Immunol 22(10):614\u2013628","journal-title":"Nat Rev Immunol"},{"issue":"7620","key":"4067_CR36","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nature19330","volume":"537","author":"SJ Im","year":"2016","unstructured":"Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC, Shan Q, Hale JS, Lee J, Nasti TH, Sharpe AH, Freeman GJ, Germain RN, Nakaya HI, Xue HH, Ahmed R (2016) Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537(7620):417\u2013421","journal-title":"Nature"},{"issue":"7930","key":"4067_CR37","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1038\/s41586-022-05257-0","volume":"610","author":"M Hashimoto","year":"2022","unstructured":"Hashimoto M, Araki K, Cardenas MA, Li P, Jadhav RR, Kissick HT, Hudson WH, McGuire DJ, Obeng RC, Wieland A, Lee J, McManus DT, Ross JL, Im SJ, Lee J, Lin JX, Hu B, West EE, Scharer CD, Freeman GJ, Sharpe AH, Ramalingam SS, Pellerin A, Teichgraber V, Greenleaf WJ, Klein C, Goronzy JJ, Umana P, Leonard WJ, Smith KA, Ahmed R (2022) PD-1 combination therapy with IL-2 modifies CD8(+) T cell exhaustion program. Nature 610(7930):173\u2013181","journal-title":"Nature"},{"issue":"4","key":"4067_CR38","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.3892\/ijo.2016.3640","volume":"49","author":"S Nishitani","year":"2016","unstructured":"Nishitani S, Noma K, Ohara T, Tomono Y, Watanabe S, Tazawa H, Shirakawa Y, Fujiwara T (2016) Iron depletion-induced downregulation of N-cadherin expression inhibits invasive malignant phenotypes in human esophageal cancer. Int J Oncol 49(4):1351\u20131359","journal-title":"Int J Oncol"},{"issue":"1","key":"4067_CR39","doi-asserted-by":"publisher","first-page":"89","DOI":"10.3390\/ijms23010089","volume":"23","author":"J Szymonik","year":"2021","unstructured":"Szymonik J, Wala K, Gornicki T, Saczko J, Pencakowski B, Kulbacka J (2021) The impact of iron chelators on the biology of cancer stem cells. Int J Mol Sci 23(1):89","journal-title":"Int J Mol Sci"},{"issue":"1","key":"4067_CR40","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s41232-022-00220-y","volume":"42","author":"W Wang","year":"2022","unstructured":"Wang W, Tabu K, Aimaitijiang A, Taga T (2022) Therapy-resistant nature of cancer stem cells in view of iron metabolism. Inflamm Regen 42(1):34","journal-title":"Inflamm Regen"},{"issue":"1","key":"4067_CR41","doi-asserted-by":"publisher","first-page":"3620","DOI":"10.1038\/s41598-024-51935-6","volume":"14","author":"K Fujii","year":"2024","unstructured":"Fujii K, Fujishima Y, Kita S, Kawada K, Fukuoka K, Sakaue TA, Okita T, Kawada-Horitani E, Nagao H, Fukuda S, Maeda N, Nishizawa H, Shimomura I (2024) Pharmacological HIF-1 activation upregulates extracellular vesicle production synergistically with adiponectin through transcriptional induction and protein stabilization of T-cadherin. Sci Rep 14(1):3620","journal-title":"Sci Rep"},{"issue":"7","key":"4067_CR42","doi-asserted-by":"publisher","first-page":"2856","DOI":"10.7150\/thno.88223","volume":"14","author":"S Madai","year":"2024","unstructured":"Madai S, Kilic P, Schmidt RM, Bas-Orth C, Korff T, Buttner M, Klinke G, Poschet G, Marti HH, Kunze R (2024) Activation of the hypoxia-inducible factor pathway protects against acute ischemic stroke by reprogramming central carbon metabolism. Theranostics 14(7):2856\u20132880","journal-title":"Theranostics"},{"issue":"4","key":"4067_CR43","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1111\/imm.13797","volume":"172","author":"Y Wang","year":"2024","unstructured":"Wang Y, Cheng Y, Zhang P, Huang D, Zhai X, Feng Z, Fang D, Liu C, Du J, Cai J (2024) FG-4592 protected haematopoietic system from ionising radiation in mice. Immunology 172(4):614\u2013626","journal-title":"Immunology"},{"issue":"1","key":"4067_CR44","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1124\/jpet.122.001126","volume":"383","author":"A Zuk","year":"2022","unstructured":"Zuk A, Si Z, Loi S, Bommegowda S, Hoivik D, Danthi S, Molnar G, Csizmadia V, Rabinowitz M (2022) Preclinical characterization of vadadustat (AKB-6548), an oral small molecule hypoxia-inducible factor prolyl-4-hydroxylase inhibitor, for the potential treatment of renal anemia. J Pharmacol Exp Ther 383(1):11\u201324","journal-title":"J Pharmacol Exp Ther"},{"key":"4067_CR45","doi-asserted-by":"publisher","first-page":"122641","DOI":"10.1016\/j.lfs.2024.122641","volume":"346","author":"T Nakai","year":"2024","unstructured":"Nakai T, Saigusa D, Kato K, Fukuuchi T, Koshiba S, Yamamoto M, Suzuki N (2024) The drug-specific properties of hypoxia-inducible factor-prolyl hydroxylase inhibitors in mice reveal a significant contribution of the kidney compared to the liver to erythropoietin induction. Life Sci 346:122641","journal-title":"Life Sci"},{"issue":"17","key":"4067_CR46","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1056\/NEJMoa2035938","volume":"384","author":"GM Chertow","year":"2021","unstructured":"Chertow GM, Pergola PE, Farag YMK, Agarwal R, Arnold S, Bako G, Block GA, Burke S, Castillo FP, Jardine AG, Khawaja Z, Koury MJ, Lewis EF, Lin T, Luo W, Maroni BJ, Matsushita K, McCullough PA, Parfrey PS, Roy-Chaudhury P, Sarnak MJ, Sharma A, Spinowitz B, Tseng C, Tumlin J, Vargo DL, Walters KA, Winkelmayer WC, Wittes J, Eckardt KU, Group PTS (2021) Vadadustat in patients with anemia and non-dialysis-dependent CKD. N Engl J Med 384(17):1589\u20131600","journal-title":"N Engl J Med"},{"issue":"3","key":"4067_CR47","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1007\/s40262-021-01095-x","volume":"61","author":"D Czock","year":"2022","unstructured":"Czock D, Keller F (2022) Clinical pharmacokinetics and pharmacodynamics of roxadustat. Clin Pharmacokinet 61(3):347\u2013362","journal-title":"Clin Pharmacokinet"},{"issue":"4","key":"4067_CR48","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2015.1062968","volume":"5","author":"G Berchem","year":"2016","unstructured":"Berchem G, Noman MZ, Bosseler M, Paggetti J, Baconnais S, Le Cam E, Nanbakhsh A, Moussay E, Mami-Chouaib F, Janji B, Chouaib S (2016) Hypoxic tumor-derived microvesicles negatively regulate NK cell function by a mechanism involving TGF-beta and miR23a transfer. Oncoimmunology 5(4):e1062968","journal-title":"Oncoimmunology"},{"issue":"6","key":"4067_CR49","doi-asserted-by":"publisher","first-page":"3720","DOI":"10.4049\/jimmunol.0900970","volume":"183","author":"EU Wieckowski","year":"2009","unstructured":"Wieckowski EU, Visus C, Szajnik M, Szczepanski MJ, Storkus WJ, Whiteside TL (2009) Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes. J Immunol 183(6):3720\u20133730","journal-title":"J Immunol"},{"issue":"1","key":"4067_CR50","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1038\/s41467-018-02865-1","volume":"9","author":"N Seo","year":"2018","unstructured":"Seo N, Shirakura Y, Tahara Y, Momose F, Harada N, Ikeda H, Akiyoshi K, Shiku H (2018) Activated CD8(+) T cell extracellular vesicles prevent tumour progression by targeting of lesional mesenchymal cells. Nat Commun 9(1):435","journal-title":"Nat Commun"},{"issue":"11","key":"4067_CR51","doi-asserted-by":"publisher","first-page":"2790","DOI":"10.1007\/s13346-023-01370-3","volume":"13","author":"S Najafi","year":"2023","unstructured":"Najafi S, Majidpoor J, Mortezaee K (2023) Extracellular vesicle-based drug delivery in cancer immunotherapy. Drug Deliv Transl Res 13(11):2790\u20132806","journal-title":"Drug Deliv Transl Res"},{"issue":"1","key":"4067_CR52","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1002\/cac2.12392","volume":"43","author":"Z Fang","year":"2023","unstructured":"Fang Z, Meng Q, Xu J, Wang W, Zhang B, Liu J, Liang C, Hua J, Zhao Y, Yu X, Shi S (2023) Signaling pathways in cancer-associated fibroblasts: recent advances and future perspectives. Cancer Commun (Lond) 43(1):3\u201341","journal-title":"Cancer Commun (Lond)"},{"issue":"2","key":"4067_CR53","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.molcel.2019.10.023","volume":"77","author":"JY Wu","year":"2020","unstructured":"Wu JY, Huang TW, Hsieh YT, Wang YF, Yen CC, Lee GL, Yeh CC, Peng YJ, Kuo YY, Wen HT, Lin HC, Hsiao CW, Wu KK, Kung HJ, Hsu YJ, Kuo CC (2020) Cancer-derived succinate promotes macrophage polarization and cancer metastasis via succinate receptor. Mol Cell 77(2):213-227e215","journal-title":"Mol Cell"}],"container-title":["Cancer Immunology, Immunotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-025-04067-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00262-025-04067-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-025-04067-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,14]],"date-time":"2025-06-14T22:01:35Z","timestamp":1749938495000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00262-025-04067-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,9]]},"references-count":53,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["4067"],"URL":"https:\/\/doi.org\/10.1007\/s00262-025-04067-3","relation":{},"ISSN":["1432-0851"],"issn-type":[{"value":"1432-0851","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,9]]},"assertion":[{"value":"28 September 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 April 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 May 2025","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 experiments involving animals were conducted according to the ethical policies and procedures approved by The Animal Care and Use Committee of Okayama University (Approved No. OKU-2021900, OKU- 2022723, OKU- 2022879, OKU- 2023535).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"192"}}