{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T21:37:07Z","timestamp":1790113027247,"version":"4.0.1"},"reference-count":293,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T00:00:00Z","timestamp":1635379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["DTS19\/00162"],"award-info":[{"award-number":["DTS19\/00162"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministerio de Ciencia, Innovacion y Universidades (MICIUN)","award":["PID2019-106386RB-I00"],"award-info":[{"award-number":["PID2019-106386RB-I00"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The concept of cancer as a systemic disease, and the therapeutic implications of this, has gained special relevance. This concept encompasses the interactions between tumor and stromal cells and their microenvironment in the complex setting of primary tumors and metastases. These factors determine cellular co-evolution in time and space, contribute to tumor progression, and could counteract therapeutic effects. Additionally, cancer therapies can induce cellular and molecular responses in the tumor and host that allow them to escape therapy and promote tumor progression. In this study, we describe the vascular network, tumor-infiltrated immune cells, and cancer-associated fibroblasts as sources of heterogeneity and plasticity in the tumor microenvironment, and their influence on cancer progression. We also discuss tumor and host responses to the chemotherapy regimen, at the maximum tolerated dose, mainly targeting cancer cells, and a multimodal metronomic chemotherapy approach targeting both cancer cells and their microenvironment. In a combination therapy context, metronomic chemotherapy exhibits antimetastatic efficacy with low toxicity but is not exempt from resistance mechanisms. As such, a better understanding of the interactions between the components of the tumor microenvironment could improve the selection of drug combinations and schedules, as well as the use of nano-therapeutic agents against certain malignancies.<\/jats:p>","DOI":"10.3390\/cancers13215414","type":"journal-article","created":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T23:50:28Z","timestamp":1635465028000},"page":"5414","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment"],"prefix":"10.3390","volume":"13","author":[{"given":"Raquel","family":"Mu\u00f1oz","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Physiology and Molecular Biology, University of Valladolid, Paseo de Bel\u00e9n, 47011 Valladolid, Spain"},{"name":"Smart Biodevices for NanoMed Group, University of Valladolid, LUCIA Building, Paseo de Bel\u00e9n, 47011 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4754-7022","authenticated-orcid":false,"given":"Alessandra","family":"Girotti","sequence":"additional","affiliation":[{"name":"BIOFORGE (Group for Advanced Materials and Nanobiotechnology), University of Valladolid, CIBER-BBN, LUCIA Building, Paseo de Bel\u00e9n, 47011 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Hileeto","sequence":"additional","affiliation":[{"name":"School of Optometry and Vision Science, University of Waterloo, Waterloo, ON N2L 361, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Javier","family":"Arias","sequence":"additional","affiliation":[{"name":"Smart Biodevices for NanoMed Group, University of Valladolid, LUCIA Building, Paseo de Bel\u00e9n, 47011 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.canlet.2019.07.010","article-title":"The tumour microenvironment as an integrated framework to understand cancer biology","volume":"461","author":"Lucantoni","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"160","DOI":"10.3389\/fmolb.2019.00160","article-title":"Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy","volume":"6","author":"Henke","year":"2019","journal-title":"Front. 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