{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T01:12:31Z","timestamp":1779153151177,"version":"3.51.4"},"reference-count":66,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":48,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["310030_208136"],"award-info":[{"award-number":["310030_208136"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-026-44611-4","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T18:34:25Z","timestamp":1775068465000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modeling optimal timing of immunotherapy and chemotherapy to prevent resistance and recurrence in triple-negative breast cancer"],"prefix":"10.1038","volume":"16","author":[{"given":"Mobina","family":"Daneshparvar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mojtaba","family":"Ghanizadeh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seyed Peyman","family":"Shariatpanahi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bahram","family":"Goliaei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reza","family":"Mehdizadeh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Curzio","family":"R\u00fcegg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"issue":"Suppl 2","key":"44611_CR1","first-page":"001","volume":"2013","author":"K Aysola","year":"2013","unstructured":"Aysola, K. et al. Triple negative breast cancer\u2013an overview. Hereditary Genet. 2013(Suppl 2), 001 (2013).","journal-title":"Hereditary Genet."},{"issue":"1","key":"44611_CR2","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1038\/s41598-024-84785-3","volume":"15","author":"T Ma","year":"2025","unstructured":"Ma, T. et al. Predictive markers of rapid disease progression and chemotherapy resistance in triple-negative breast cancer patients following postoperative adjuvant therapy. Sci. Rep. 15(1), 386 (2025).","journal-title":"Sci. Rep."},{"issue":"6","key":"44611_CR3","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.3892\/ijo.2020.5135","volume":"57","author":"K-A Won","year":"2020","unstructured":"Won, K.-A. & Spruck, C. Triple-negative breast cancer therapy: Current and future perspectives. Int. J. Oncol. 57(6), 1245\u201361 (2020).","journal-title":"Int. J. Oncol."},{"issue":"6","key":"44611_CR4","doi-asserted-by":"publisher","DOI":"10.37349\/etat.2023.00190","volume":"4","author":"Z Guo","year":"2023","unstructured":"Guo, Z. & Han, S. Targeting cancer stem cell plasticity in triple-negative breast cancer. Explor. Target. Antitumor Ther. 4(6), 1165 (2023).","journal-title":"Explor. Target. Antitumor Ther."},{"key":"44611_CR5","doi-asserted-by":"crossref","unstructured":"Peyvandi, S., Bulliard, M., Yilmaz, A., Kauzlaric, A., Marcone, R., Haerri, L., et al. Tumor-educated Gr1\u2009+\u2009CD11b+ cells drive breast cancer metastasis via OSM\/IL-6\/JAK\u2013induced cancer cell plasticity. J. Clin. Invest. 134(6) (2024).","DOI":"10.1172\/JCI166847"},{"issue":"19","key":"44611_CR6","doi-asserted-by":"publisher","first-page":"7820","DOI":"10.1073\/pnas.1103441108","volume":"108","author":"G Upadhyay","year":"2011","unstructured":"Upadhyay, G. et al. Stem cell antigen-1 enhances tumorigenicity by disruption of growth differentiation factor-10 (GDF10)\u2013dependent TGF-\u03b2 signaling. Proc. Natl. Acad. Sci. U. S. A. 108(19), 7820\u20137825 (2011).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"1","key":"44611_CR7","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.ajpath.2011.03.005","volume":"179","author":"MA Velasco-Vel\u00e1zquez","year":"2011","unstructured":"Velasco-Vel\u00e1zquez, M. A., Popov, V. M., Lisanti, M. P. & Pestell, R. G. The role of breast cancer stem cells in metastasis and therapeutic implications. Am. J. Pathol. 179(1), 2\u201311 (2011).","journal-title":"Am. J. Pathol."},{"issue":"9","key":"44611_CR8","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines10091493","volume":"10","author":"AG Mukherjee","year":"2022","unstructured":"Mukherjee, A. G. et al. Role of immune cells and receptors in cancer treatment: an immunotherapeutic approach. Vaccines 10(9), 1493 (2022).","journal-title":"Vaccines"},{"key":"44611_CR9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.679117","volume":"12","author":"KA Shaver","year":"2021","unstructured":"Shaver, K. A., Croom-Perez, T. J. & Copik, A. J. Natural killer cells: The linchpin for successful cancer immunotherapy. Front. Immunol. 12, 679117 (2021).","journal-title":"Front. Immunol."},{"issue":"1","key":"44611_CR10","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms12010230","volume":"12","author":"A Vojdani","year":"2024","unstructured":"Vojdani, A. et al. Natural killer cells and cytotoxic T cells: Complementary partners against microorganisms and cancer. Microorganisms 12(1), 230 (2024).","journal-title":"Microorganisms"},{"issue":"1","key":"44611_CR11","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1146\/annurev-cancerbio-030617-050606","volume":"2","author":"S Spranger","year":"2018","unstructured":"Spranger, S. & Gajewski, T. F. Mechanisms of tumor cell\u2013intrinsic immune evasion. Annu. Rev. Cancer Biol. 2(1), 213\u2013228 (2018).","journal-title":"Annu. Rev. Cancer Biol."},{"issue":"2","key":"44611_CR12","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13020210","volume":"13","author":"M Haist","year":"2021","unstructured":"Haist, M., Stege, H., Grabbe, S. & Bros, M. The functional crosstalk between myeloid-derived suppressor cells and regulatory T cells within the immunosuppressive tumor microenvironment. Cancers 13(2), 210 (2021).","journal-title":"Cancers"},{"issue":"11","key":"44611_CR13","doi-asserted-by":"publisher","first-page":"2912","DOI":"10.3390\/cancers15112912","volume":"15","author":"C Sordo-Bahamonde","year":"2023","unstructured":"Sordo-Bahamonde, C. et al. Chemo-immunotherapy: A new trend in cancer treatment. Cancers 15(11), 2912 (2023).","journal-title":"Cancers"},{"key":"44611_CR14","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1405491","volume":"14","author":"N Xiong","year":"2024","unstructured":"Xiong, N., Wu, H. & Yu, Z. Advancements and challenges in triple-negative breast cancer: A comprehensive review of therapeutic and diagnostic strategies. Front. Oncol. 14, 1405491 (2024).","journal-title":"Front. Oncol."},{"key":"44611_CR15","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/0065-2571(94)90025-6","volume":"34","author":"F Huennekens","year":"1994","unstructured":"Huennekens, F. The methotrexate story: A paradigm for development of cancer chemotherapeutic agents. Adv. Enzyme Regul. 34, 397\u2013419 (1994).","journal-title":"Adv. Enzyme Regul."},{"issue":"18","key":"44611_CR16","doi-asserted-by":"publisher","first-page":"2966","DOI":"10.1200\/JCO.2009.25.9549","volume":"28","author":"M Colleoni","year":"2010","unstructured":"Colleoni, M. et al. Classical cyclophosphamide, methotrexate, and fluorouracil chemotherapy is more effective in triple-negative, node-negative breast cancer: Results from two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer. J. Clin. Oncol. 28(18), 2966\u201373 (2010).","journal-title":"J. Clin. Oncol."},{"issue":"2","key":"44611_CR17","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1093\/annonc\/mdr309","volume":"23","author":"E Munzone","year":"2012","unstructured":"Munzone, E., Curigliano, G., Burstein, H., Winer, E. & Goldhirsch, A. CMF revisited in the 21st century. Ann. Oncol. 23(2), 305\u2013311 (2012).","journal-title":"Ann. Oncol."},{"key":"44611_CR18","doi-asserted-by":"crossref","unstructured":"Bocci, G., et al. Cyclophosphamide-methotrexate \u2018metronomic\u2019chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation. Annals Oncol. 16(8), 1243\u20131252 (2005).","DOI":"10.1093\/annonc\/mdi240"},{"issue":"1","key":"44611_CR19","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1093\/annonc\/mdf013","volume":"13","author":"M Colleoni","year":"2002","unstructured":"Colleoni, M. et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: Antitumor activity and correlation with vascular endothelial growth factor levels. Ann. Oncol. 13(1), 73\u201380 (2002).","journal-title":"Ann. Oncol."},{"key":"44611_CR20","doi-asserted-by":"publisher","unstructured":"Lora, M. et al. Low dose methotrexate has divergent effects on cycling and resting human hematopoietic stem and progenitor cells. Clin. Transl. Sci. 18(5), e70233. https:\/\/doi.org\/10.1111\/cts.70233 (2025).","DOI":"10.1111\/cts.70233"},{"issue":"2","key":"44611_CR21","first-page":"530","volume":"42","author":"I Pannacciulli","year":"1982","unstructured":"Pannacciulli, I., Massa, G., Bogliolo, G., Ghio, R. & Sobrero, A. Effects of high-dose methotrexate and leucovorin on murine hemopoietic stem cells. Cancer Res. 42(2), 530\u2013534 (1982).","journal-title":"Cancer Res."},{"issue":"21","key":"44611_CR22","doi-asserted-by":"publisher","first-page":"5205","DOI":"10.3390\/cancers14215205","volume":"14","author":"SP Ling","year":"2022","unstructured":"Ling, S. P. et al. Role of immunotherapy in the treatment of cancer: A systematic review. Cancers 14(21), 5205 (2022).","journal-title":"Cancers"},{"key":"44611_CR23","doi-asserted-by":"crossref","unstructured":"Lim, E., et al. Abstract CT146: RGX-104, a first-in-class immunotherapy targeting the liver-X receptor (LXR): initial results from the phase 1b RGX-104 plus docetaxel combination dose escalation cohorts. Cancer Res. 80(16_Supplement), CT146-CT (2020).","DOI":"10.1158\/1538-7445.AM2020-CT146"},{"issue":"4","key":"44611_CR24","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1016\/j.cell.2017.12.026","volume":"172","author":"MF Tavazoie","year":"2018","unstructured":"Tavazoie, M. F. et al. LXR\/ApoE activation restricts innate immune suppression in cancer. Cell 172(4), 825\u201340. e18 (2018).","journal-title":"Cell"},{"key":"44611_CR25","doi-asserted-by":"publisher","first-page":"1513421","DOI":"10.3389\/fimmu.2024.1513421","volume":"15","author":"L Serrano Garc\u00eda","year":"2024","unstructured":"Serrano Garc\u00eda, L. et al. Patterns of immune evasion in triple-negative breast cancer and new potential therapeutic targets: a review. Front. Immunol. 15, 1513421 (2024).","journal-title":"Front. Immunol."},{"issue":"8","key":"44611_CR26","doi-asserted-by":"publisher","first-page":"1785","DOI":"10.3390\/cells9081785","volume":"9","author":"YJ Cha","year":"2020","unstructured":"Cha, Y. J. & Koo, J. S. Role of tumor-associated myeloid cells in breast cancer. Cells 9(8), 1785 (2020).","journal-title":"Cells"},{"issue":"9","key":"44611_CR27","doi-asserted-by":"publisher","first-page":"957","DOI":"10.3390\/cells8090957","volume":"8","author":"M Nedeljkovi\u0107","year":"2019","unstructured":"Nedeljkovi\u0107, M. & Damjanovi\u0107, A. Mechanisms of chemotherapy resistance in triple-negative breast cancer\u2014How we can rise to the challenge. Cells 8(9), 957 (2019).","journal-title":"Cells"},{"issue":"11","key":"44611_CR28","doi-asserted-by":"publisher","first-page":"4894","DOI":"10.1158\/0008-5472.CAN-08-3658","volume":"69","author":"RA Gatenby","year":"2009","unstructured":"Gatenby, R. A., Silva, A. S., Gillies, R. J. & Frieden, B. R. Adaptive therapy. Cancer Res. 69(11), 4894\u2013903 (2009).","journal-title":"Cancer Res."},{"issue":"1925","key":"44611_CR29","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.2019.2454","volume":"287","author":"M Gluzman","year":"2020","unstructured":"Gluzman, M., Scott, J. G. & Vladimirsky, A. Optimizing adaptive cancer therapy: Dynamic programming and evolutionary game theory. Proc. R. Soc. B Biol. Sci. 287(1925), 20192454 (2020).","journal-title":"Proc. R. Soc. B Biol. Sci."},{"issue":"1","key":"44611_CR30","volume":"2016","author":"PH Pandya","year":"2016","unstructured":"Pandya, P. H., Murray, M. E., Pollok, K. E. & Renbarger, J. L. The immune system in cancer pathogenesis: Potential therapeutic approaches. J. Immunol. Res. 2016(1), 4273943 (2016).","journal-title":"J. Immunol. Res."},{"issue":"1","key":"44611_CR31","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/S0025-5564(97)00080-1","volume":"147","author":"JC Panetta","year":"1998","unstructured":"Panetta, J. C. A mathematical model of drug resistance: Heterogeneous tumors. Math. Biosci. 147(1), 41\u201361 (1998).","journal-title":"Math. Biosci."},{"issue":"11","key":"44611_CR32","doi-asserted-by":"publisher","first-page":"2627","DOI":"10.1016\/j.bbagen.2016.06.009","volume":"1860","author":"RH Chisholm","year":"2016","unstructured":"Chisholm, R. H., Lorenzi, T. & Clairambault, J. Cell population heterogeneity and evolution towards drug resistance in cancer: Biological and mathematical assessment, theoretical treatment optimisation. Biochim. Biophys. Acta Gen. Subj. 1860(11), 2627\u201345 (2016).","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"issue":"1","key":"44611_CR33","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-32554-z","volume":"13","author":"R Mehdizadeh","year":"2023","unstructured":"Mehdizadeh, R., Shariatpanahi, S. P., Goliaei, B. & R\u00fcegg, C. Targeting myeloid-derived suppressor cells in combination with tumor cell vaccination predicts anti-tumor immunity and breast cancer dormancy: An in silico experiment. Sci. Rep. 13(1), 5875 (2023).","journal-title":"Sci. Rep."},{"issue":"2","key":"44611_CR34","doi-asserted-by":"publisher","first-page":"245","DOI":"10.3390\/cancers13020245","volume":"13","author":"R Mehdizadeh","year":"2021","unstructured":"Mehdizadeh, R., Shariatpanahi, S. P., Goliaei, B., Peyvandi, S. & R\u00fcegg, C. Dormant tumor cell vaccination: A mathematical model of immunological dormancy in triple-negative breast cancer. Cancers 13(2), 245 (2021).","journal-title":"Cancers"},{"issue":"10","key":"44611_CR35","doi-asserted-by":"publisher","DOI":"10.3390\/jpm11101031","volume":"11","author":"N Mohammad Mirzaei","year":"2021","unstructured":"Mohammad Mirzaei, N. et al. A mathematical model of breast tumor progression based on immune infiltration. J. Pers. Med. 11(10), 1031 (2021).","journal-title":"J. Pers. Med."},{"issue":"1","key":"44611_CR36","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s11538-022-01108-1","volume":"85","author":"AA Davenport","year":"2023","unstructured":"Davenport, A. A. et al. Mathematical model of triple-negative breast cancer in response to combination chemotherapies. Bull. Math. Biol. 85(1), 7 (2023).","journal-title":"Bull. Math. Biol."},{"issue":"5","key":"44611_CR37","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12051087","volume":"12","author":"J Shen","year":"2020","unstructured":"Shen, J., Li, L., Howlett, N. G., Cohen, P. S. & Sun, G. Application of a biphasic mathematical model of cancer cell drug response for formulating potent and synergistic targeted drug combinations to triple negative breast cancer cells. Cancers 12(5), 1087 (2020).","journal-title":"Cancers"},{"issue":"11","key":"44611_CR38","doi-asserted-by":"publisher","first-page":"2410","DOI":"10.3390\/math11112410","volume":"11","author":"JC L\u00f3pez-Alvarenga","year":"2023","unstructured":"L\u00f3pez-Alvarenga, J. C. et al. A mathematical model to optimize the neoadjuvant chemotherapy treatment sequence for triple-negative locally advanced breast cancer. Mathematics 11(11), 2410 (2023).","journal-title":"Mathematics"},{"issue":"19\u201320","key":"44611_CR39","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1101\/gad.314617.118","volume":"32","author":"H Gonzalez","year":"2018","unstructured":"Gonzalez, H., Hagerling, C. & Werb, Z. Roles of the immune system in cancer: From tumor initiation to metastatic progression. Genes Dev. 32(19\u201320), 1267\u20131284 (2018).","journal-title":"Genes Dev."},{"issue":"10","key":"44611_CR40","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/nri.2016.80","volume":"16","author":"DE Speiser","year":"2016","unstructured":"Speiser, D. E., Ho, P.-C. & Verdeil, G. Regulatory circuits of T cell function in cancer. Nat. Rev. Immunol. 16(10), 599\u2013611 (2016).","journal-title":"Nat. Rev. Immunol."},{"issue":"8","key":"44611_CR41","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1007\/s11605-017-3446-6","volume":"21","author":"M Donadon","year":"2017","unstructured":"Donadon, M. et al. Increased infiltration of natural killer and T cells in colorectal liver metastases improves patient overall survival. J. Gastrointest. Surg. 21(8), 1226\u20131236 (2017).","journal-title":"J. Gastrointest. Surg."},{"key":"44611_CR42","doi-asserted-by":"publisher","DOI":"10.1016\/j.chaos.2021.111349","volume":"152","author":"M Ghanizadeh","year":"2021","unstructured":"Ghanizadeh, M., Shariatpanahi, S. P., Goliaei, B. & R\u00fcegg, C. Mathematical modeling approach of cancer immunoediting reveals new insights in targeted-therapy and timing plan of cancer treatment. Chaos Solitons Fractals 152, 111349 (2021).","journal-title":"Chaos Solitons Fractals"},{"issue":"01","key":"44611_CR43","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1142\/S0218339020500035","volume":"28","author":"D He","year":"2020","unstructured":"He, D., Xu, W., Li, X. & Xu, J.-X. A prognostic immunotherapy model for 4T1 breast cancer with combined cyclophosphamide and TLR agonist. J. Biol. Syst. 28(01), 65\u201390 (2020).","journal-title":"J. Biol. Syst."},{"issue":"8","key":"44611_CR44","doi-asserted-by":"publisher","first-page":"1654","DOI":"10.1002\/jps.10431","volume":"92","author":"ED Lobo","year":"2003","unstructured":"Lobo, E. D. & Balthasar, J. P. Pharmacokinetic\u2013pharmacodynamic modeling of methotrexate-induced toxicity in mice. J. Pharm. Sci. 92(8), 1654\u201364 (2003).","journal-title":"J. Pharm. Sci."},{"key":"44611_CR45","first-page":"606","volume":"232","author":"FA Rihan","year":"2014","unstructured":"Rihan, F. A., Rahman, D. A., Lakshmanan, S. & Alkhajeh, A. A time delay model of tumour\u2013immune system interactions: Global dynamics, parameter estimation, sensitivity analysis. Appl. Math. Comput. 232, 606\u201323 (2014).","journal-title":"Appl. Math. Comput."},{"issue":"2","key":"44611_CR46","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/bjc.2016.171","volume":"115","author":"Y Yamamoto","year":"2016","unstructured":"Yamamoto, Y. et al. Tumour and immune cell dynamics explain the PSA bounce after prostate cancer brachytherapy. Br. J. Cancer 115(2), 195\u2013202 (2016).","journal-title":"Br. J. Cancer"},{"issue":"1","key":"44611_CR47","doi-asserted-by":"publisher","DOI":"10.1186\/1479-5876-7-102","volume":"7","author":"BJ Coventry","year":"2009","unstructured":"Coventry, B. J. et al. CRP identifies homeostatic immune oscillations in cancer patients: A potential treatment targeting tool?. J. Transl. Med. 7(1), 102 (2009).","journal-title":"J. Transl. Med."},{"issue":"1","key":"44611_CR48","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/S0145-2126(02)00097-8","volume":"27","author":"Z Xiao","year":"2003","unstructured":"Xiao, Z., Hao, Y., Qin, T. & Han, Z. Periodic oscillation of blood leukocytes, platelets, and hemoglobin in a patient with chronic eosinophilic leukemia. Leuk. Res. 27(1), 89\u201391 (2003).","journal-title":"Leuk. Res."},{"issue":"1","key":"44611_CR49","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1186\/s13014-019-1423-9","volume":"14","author":"S Tubin","year":"2019","unstructured":"Tubin, S., Ashdown, M. & Jeremic, B. Time-synchronized immune-guided SBRT partial bulky tumor irradiation targeting hypoxic segment while sparing the peritumoral immune microenvironment. Radiat. Oncol. 14(1), 220 (2019).","journal-title":"Radiat. Oncol."},{"key":"44611_CR50","first-page":"958","volume":"4","author":"A Croghan","year":"2012","unstructured":"Croghan, A. & Markovic, S. N. Fluctuation of systemic immunity in melanoma and implications for timing of therapy Alexey A. Leontovich2, Roxana S. Dronca3, Vera J. Suman2, Martin L. Ashdown4, Wendy K. Nevala1, Michael A. Thompson1, Andrew Robinson5, Lisa A. Kottschade3, Judith S. Kaur3, Robert R. McWilliams3, Leonid V. Ivanov6, Gary. Front. Biosci. 4, 958\u201375 (2012).","journal-title":"Front. Biosci."},{"key":"44611_CR51","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40169-018-0185-6","volume":"7","author":"H Maeda","year":"2018","unstructured":"Maeda, H. & Khatami, M. Analyses of repeated failures in cancer therapy for solid tumors: Poor tumor-selective drug delivery, low therapeutic efficacy and unsustainable costs. Clin. Transl. Med. 7, 1\u201320 (2018).","journal-title":"Clin. Transl. Med."},{"issue":"2","key":"44611_CR52","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1007\/s11538-023-01247-z","volume":"86","author":"A Arabameri","year":"2024","unstructured":"Arabameri, A. & Arab, S. Understanding the interplay of CAR-NK cells and triple-negative breast cancer: Insights from computational modeling. Bull. Math. Biol. 86(2), 20 (2024).","journal-title":"Bull. Math. Biol."},{"issue":"7","key":"44611_CR53","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1038\/s41590-024-01859-0","volume":"25","author":"BM Fortin","year":"2024","unstructured":"Fortin, B. M. et al. Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade. Nat. Immunol. 25(7), 1257\u20131269 (2024).","journal-title":"Nat. Immunol."},{"issue":"1","key":"44611_CR54","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1007\/s12672-024-01643-4","volume":"15","author":"M El-Tanani","year":"2024","unstructured":"El-Tanani, M. et al. Circadian rhythms and cancer: implications for timing in therapy. Discov. Oncol. 15(1), 767 (2024).","journal-title":"Discov. Oncol."},{"issue":"1","key":"44611_CR55","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/s41420-024-01960-1","volume":"10","author":"Y Zeng","year":"2024","unstructured":"Zeng, Y., Guo, Z., Wu, M., Chen, F. & Chen, L. Circadian rhythm regulates the function of immune cells and participates in the development of tumors. Cell Death Discov. 10(1), 199 (2024).","journal-title":"Cell Death Discov."},{"issue":"11","key":"44611_CR56","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1001\/jamaoto.2019.2414","volume":"145","author":"DZ Liao","year":"2019","unstructured":"Liao, D. Z. et al. Association of delayed time to treatment initiation with overall survival and recurrence among patients with head and neck squamous cell carcinoma in an underserved urban population. JAMA Otolaryngol. Head Neck Surg. 145(11), 1001\u20131009 (2019).","journal-title":"JAMA Otolaryngol. Head Neck Surg."},{"issue":"7","key":"44611_CR57","doi-asserted-by":"publisher","first-page":"1578","DOI":"10.1158\/0008-5472.CAN-19-2669","volume":"80","author":"J West","year":"2020","unstructured":"West, J. et al. Towards multidrug adaptive therapy. Cancer Res. 80(7), 1578\u20131589 (2020).","journal-title":"Cancer Res."},{"issue":"11","key":"44611_CR58","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1038\/s41571-020-0411-1","volume":"17","author":"RA Gatenby","year":"2020","unstructured":"Gatenby, R. A. & Brown, J. S. Integrating evolutionary dynamics into cancer therapy. Nat. Rev. Clin. Oncol. 17(11), 675\u2013686 (2020).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"44611_CR59","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1007\/s10549-015-3405-4","volume":"151","author":"F Petrelli","year":"2015","unstructured":"Petrelli, F. et al. Adjuvant dose-dense chemotherapy in breast cancer: a systematic review and meta-analysis of randomized trials. Breast Cancer Res. Treat. 151, 251\u2013259 (2015).","journal-title":"Breast Cancer Res. Treat."},{"issue":"9","key":"44611_CR60","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1093\/jnci\/dji114","volume":"97","author":"P Lorigan","year":"2005","unstructured":"Lorigan, P. et al. Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer. J. Natl. Cancer Inst. 97(9), 666\u2013674 (2005).","journal-title":"J. Natl. Cancer Inst."},{"key":"44611_CR61","doi-asserted-by":"crossref","unstructured":"Kang, D.H. et al. The rest period between chemotherapy and immunotherapy influences the efficacy of immune checkpoint inhibitors in lung cancer. Thorac Cancer. 13(16), 2346\u20132354 (2022).","DOI":"10.1111\/1759-7714.14568"},{"key":"44611_CR62","first-page":"N\/A","volume":"5","author":"S Peyvandi","year":"2019","unstructured":"Peyvandi, S., Lan, Q., Lorusso, G. & R\u00fcegg, C. Chemotherapy-induced immunological breast cancer dormancy: a new function for old drugs?. JCMT 5, N\/A-N\/A (2019).","journal-title":"JCMT"},{"key":"44611_CR63","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.jconrel.2021.01.009","volume":"331","author":"M Kwon","year":"2021","unstructured":"Kwon, M., Jung, H., Nam, G.-H. & Kim, I.-S. The right timing, right combination, right sequence, and right delivery for cancer immunotherapy. JCR 331, 321\u2013334 (2021).","journal-title":"JCR"},{"key":"44611_CR64","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jtbi.2018.01.006","volume":"442","author":"SP Shariatpanahi","year":"2018","unstructured":"Shariatpanahi, S. P., Shariatpanahi, S. P., Madjidzadeh, K., Hassan, M. & Abedi-Valugerdi, M. Mathematical modeling of tumor-induced immunosuppression by myeloid-derived suppressor cells: Implications for therapeutic targeting strategies. J Theor Biol 442, 1\u201310 (2018).","journal-title":"J Theor Biol"},{"issue":"5","key":"44611_CR65","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0178479","volume":"12","author":"X Lai","year":"2017","unstructured":"Lai, X. & Friedman, A. Combination therapy of cancer with cancer vaccine and immune checkpoint inhibitors: A mathematical model. PLoS One 12(5), e0178479 (2017).","journal-title":"PLoS One"},{"issue":"23","key":"44611_CR66","doi-asserted-by":"publisher","first-page":"38022","DOI":"10.18632\/oncotarget.16723","volume":"8","author":"RB Mokhtari","year":"2017","unstructured":"Mokhtari, R. B. et al. Combination therapy in combating cancer. Oncotarget 8(23), 38022 (2017).","journal-title":"Oncotarget"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-44611-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-44611-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-44611-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T01:01:57Z","timestamp":1779152517000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-44611-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,1]]},"references-count":66,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["44611"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-44611-4","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-6963681\/v1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,1]]},"assertion":[{"value":"24 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 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":"Competing interests"}}],"article-number":"15450"}}