{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T13:26:35Z","timestamp":1792589195493,"version":"4.5.0"},"reference-count":230,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,17]],"date-time":"2022-02-17T00:00:00Z","timestamp":1645056000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health","award":["\u201cRicerca Corrente 2021\u201d and \u201c5 per mille\u201d (project 5M-2018-23680422)"],"award-info":[{"award-number":["\u201cRicerca Corrente 2021\u201d and \u201c5 per mille\u201d (project 5M-2018-23680422)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>In recent years, immunotherapy has emerged as a promising novel therapeutic strategy for cancer treatment. In a relevant percentage of patients, however, clinical benefits are lower than expected, pushing researchers to deeply analyze the immune responses against tumors and find more reliable and efficient tools to predict the individual response to therapy. Novel tissue engineering strategies can be adopted to realize in vitro fully humanized matrix-based models, as a compromise between standard two-dimensional (2D) cell cultures and animal tests, which are costly and hardly usable in personalized medicine. In this review, we describe the main mechanisms allowing cancer cells to escape the immune surveillance, which may play a significant role in the failure of immunotherapies. In particular, we discuss the role of the tumor microenvironment (TME) in the establishment of a milieu that greatly favors cancer malignant progression and impact on the interactions with immune cells. Then, we present an overview of the recent in vitro engineered preclinical three-dimensional (3D) models that have been adopted to resemble the interplays between cancer and immune cells and for testing current therapies and immunotherapeutic approaches. Specifically, we focus on 3D hydrogel-based tools based on different types of polymers, discussing the suitability of each of them in reproducing the TME key features based on their intrinsic or tunable characteristics. Finally, we introduce the possibility to combine the 3D models with technological fluid dynamics platforms, reproducing the dynamic complex interactions between tumor cells and immune effectors migrated in situ via the systemic circulation, pointing out the challenges that still have to be overcome for setting more predictive preclinical assays.<\/jats:p>","DOI":"10.3390\/cancers14041013","type":"journal-article","created":{"date-parts":[[2022,2,17]],"date-time":"2022-02-17T20:24:26Z","timestamp":1645129466000},"page":"1013","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Tumor Microenvironment and Hydrogel-Based 3D Cancer Models for In Vitro Testing Immunotherapies"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2865-1281","authenticated-orcid":false,"given":"Chiara","family":"Vitale","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Marzagalli","sequence":"additional","affiliation":[{"name":"React4life SRL, 16121 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9464-3554","authenticated-orcid":false,"given":"Silvia","family":"Scaglione","sequence":"additional","affiliation":[{"name":"React4life SRL, 16121 Genova, Italy"},{"name":"National Research Council of Italy, Institute of Electronics, Information Engineering and Telecommunications (IEIIT), 16149 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Dondero","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6695-1739","authenticated-orcid":false,"given":"Cristina","family":"Bottino","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy"},{"name":"IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2806-1115","authenticated-orcid":false,"given":"Roberta","family":"Castriconi","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1158\/2159-8290.CD-20-1680","article-title":"The next decade of immune checkpoint therapy","volume":"11","author":"Sharma","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1084\/jem.20182395","article-title":"Development of immune checkpoint therapy for cancer","volume":"216","author":"Fritz","year":"2019","journal-title":"J. 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