{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:05:14Z","timestamp":1782281114006,"version":"3.54.5"},"posted":{"date-parts":[[2025,11,18]]},"group-title":"Immunology","reference-count":85,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH","award":["NIH R01CA247441, U01CA261842 and R01CA284603"],"award-info":[{"award-number":["NIH R01CA247441, U01CA261842 and R01CA284603"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>T cell distribution within tumors (\u201ctumor hotness\u201d) critically determines immunotherapy success. However, despite numerous strategies to enhance intratumoral T cell accumulation\u2014such as multi-target CAR-Ts and combinatorial approaches\u2014limited mechanistic understanding of T cell\u2013microenvironment interactions has constrained progress. To address this, we developed a physiological mechanistic model of the 3D tumor microenvironment (TME) to evaluate CAR-T performance under environmental fluctuations and different infusion strategies. The model integrates key vascular (rolling, adhesion, endothelial suppression) and interstitial (ECM density, metabolic competition, chemokine sensitivity) barriers. Our simulations reveal that collagen density and metabolic competition dominate CAR-T efficacy. Enhancing vascular adhesion improves infiltration but remains limited by collagen and metabolism. Endothelial suppression markedly reduces tumor hotness, while its alleviation enhances response. Systemic infusion yields higher tumor hotness than intratumoral delivery, but combined routes or reduced collagen restore efficacy even in dense tumors. This mechanistic framework enables rational optimization of CAR-T strategies.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>The success of immunotherapies such as CAR-T cells depends on their ability to infiltrate and persist within solid tumors, yet the mechanisms that govern this process remain poorly understood. Using a mechanistic 3D model of the tumor microenvironment, we quantitatively dissected how vascular and interstitial barriers\u2014including endothelial suppression, collagen density, metabolic competition, and chemokine cues\u2014shape CAR-T distribution (\u201ctumor hotness\u201d). Our results reveal that stromal and metabolic constraints, rather than vascular adhesion alone, dominate CAR-T efficacy. This framework bridges molecular, cellular, and tissue-scale mechanisms, providing a quantitative foundation for optimizing CAR-T design and delivery strategies to overcome resistance in solid tumors.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.17.688869","type":"posted-content","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T17:35:21Z","timestamp":1763487321000},"source":"Crossref","is-referenced-by-count":0,"title":["A Hybrid Multiscale Model for Predicting CAR-T Therapy Outcomes in Solid Tumors"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9016-1830","authenticated-orcid":false,"given":"Mohammad R.","family":"Nikmaneshi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0698-7232","authenticated-orcid":false,"given":"Lance L.","family":"Munn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025112100300705000_2025.11.17.688869v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-02875-1"},{"key":"2025112100300705000_2025.11.17.688869v1.2","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/s41392-024-01979-x","article-title":"Cold and hot tumors: from molecular mechanisms to targeted therapy","volume":"9","year":"2024","journal-title":"Signal transduction and targeted therapy"},{"key":"2025112100300705000_2025.11.17.688869v1.3","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/s41392-025-02280-1","article-title":"Immune evasion in cancer: mechanisms and cutting-edge therapeutic approaches","volume":"10","year":"2025","journal-title":"Signal Transduction and Targeted Therapy"},{"key":"2025112100300705000_2025.11.17.688869v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(96)79248-2"},{"key":"2025112100300705000_2025.11.17.688869v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(95)80087-1"},{"key":"2025112100300705000_2025.11.17.688869v1.6","doi-asserted-by":"crossref","first-page":"635263","DOI":"10.3389\/fcell.2021.635263","article-title":"Elucidating the biomechanics of leukocyte transendothelial migration by quantitative imaging","volume":"9","year":"2021","journal-title":"Frontiers in cell and developmental biology"},{"key":"2025112100300705000_2025.11.17.688869v1.7","doi-asserted-by":"crossref","unstructured":"Carlos, T. 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