{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T05:12:37Z","timestamp":1778130757223,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1013163","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T00:00:00Z","timestamp":1750896000000}}],"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T00:00:00Z","timestamp":1749686400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01-CA259253, R01-CA208205, R01-NS118929, U01-CA261842, U01-CA224348, and the Outstanding Investigator Award R35-CA197743."],"award-info":[{"award-number":["R01-CA259253, R01-CA208205, R01-NS118929, U01-CA261842, U01-CA224348, and the Outstanding Investigator Award R35-CA197743."]}]},{"name":"National Foundation for Cancer Research, Jane\u2019s Trust Foundation, Niles Albright Research Foundation, and the Harvard Ludwig Cancer Center"},{"name":"NIH","award":["R01-CA2044949"],"award-info":[{"award-number":["R01-CA2044949"]}]},{"name":"European Research Council","award":["ERC-2019-CoG-863955"],"award-info":[{"award-number":["ERC-2019-CoG-863955"]}]},{"name":"Research and Innovation Foundation of Cyprus","award":["CULTURE\/AWARD-YR\/0523 B\/0004"],"award-info":[{"award-number":["CULTURE\/AWARD-YR\/0523 B\/0004"]}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>The success of mRNA vaccines against infectious diseases such as COVID-19 has opened new avenues for their application in oncology. In cancer immunotherapy, mRNA vaccines\u2014typically encapsulated in lipid nanoparticles (LNPs) 100\u2013200\u2009nm in size\u2014enable delivery of tumor-specific antigens to activate immune responses. Here, we investigated the efficacy of mRNA vaccines in cancer by modeling tumor-immune interactions and tumor microenvironment (TME) dynamics to identify predictive biomarkers. Using a mechanistic mathematical model, we simulated tumor growth, immune cell dynamics, and vaccine pharmacokinetics in virtual cohorts of 1,635 patients generated via Latin hypercube sampling. Our simulations demonstrated a 45% average tumor size reduction and a 60% increase in CD8\u2009+\u2009T cell infiltration in responsive tumors. Multiple regression analyses validated the predictive power of both pre- and on-treatment biomarkers. Key predictors of vaccine efficacy included antigen-presenting cell (APC) density and cytotoxic T cell fraction. Specifically, an APC density above 500 cells\/mm\u00b3 in lymph nodes correlated with a 55% increase in vaccine response rates, while a cytotoxic T cell fraction above 20% in tumors was associated with a 60% reduction in tumor volume. A reduced M2\/M1 macrophage ratio further improved treatment outcomes by 50%, highlighting the role of reprograming immunosuppressive macrophages. TME characteristics significantly influenced vaccine efficacy. Low extracellular matrix (ECM) density\u2014modeled as a 5\u201310\u2009\u00d7\u2009increase in hydraulic conductivity\u2014combined with medium cytokine levels (IL-2 and TNF-\u03b1 at 10\u201350 pg\/ml), created optimal conditions for immune activation. Under these conditions, vaccine uptake improved by 35% and cytotoxic T cell infiltration increased by 65%, resulting in up to a 50% improvement in therapeutic outcomes. Model predictions aligned with pre-clinical data from melanoma and breast cancer models. These findings provide a framework for optimizing mRNA vaccine strategies and advancing personalized cancer immunotherapy.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1013163","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T17:46:32Z","timestamp":1749750392000},"page":"e1013163","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Biomarkers of mRNA vaccine efficacy derived from mechanistic modeling of tumor-immune interactions"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3172-9489","authenticated-orcid":true,"given":"Chrysovalantis","family":"Voutouri","sequence":"first","affiliation":[]},{"given":"Lance L.","family":"Munn","sequence":"additional","affiliation":[]},{"given":"Triantafyllos","family":"Stylianopoulos","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7571-3548","authenticated-orcid":true,"given":"Rakesh K.","family":"Jain","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2025,6,12]]},"reference":[{"issue":"1","key":"pcbi.1013163.ref001","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/s43856-025-00882-y","article-title":"Effectiveness of a single COVID-19 mRNA vaccine dose in individuals with prior SARS-CoV-2 infection: a systematic review","volume":"5","author":"HR Volkman","year":"2025","journal-title":"Commun Med (Lond)"},{"issue":"1","key":"pcbi.1013163.ref002","article-title":"Systematic review and meta-analysis of COVID-19 mRNA vaccine effectiveness against hospitalizations in adults","volume":"4","author":"BK-F Wong","year":"2024","journal-title":"Immunother Adv"},{"issue":"8","key":"pcbi.1013163.ref003","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1038\/s41568-023-00586-2","article-title":"mRNA-based cancer therapeutics","volume":"23","author":"C Liu","year":"2023","journal-title":"Nat Rev Cancer"},{"issue":"3","key":"pcbi.1013163.ref004","doi-asserted-by":"crossref","first-page":"658","DOI":"10.3390\/vaccines11030658","article-title":"Recent Advances in the Lipid Nanoparticle-Mediated Delivery of mRNA Vaccines","volume":"11","author":"K Swetha","year":"2023","journal-title":"Vaccines (Basel)"},{"issue":"2","key":"pcbi.1013163.ref005","doi-asserted-by":"crossref","first-page":"186","DOI":"10.3390\/vaccines12020186","article-title":"Lipid Nanoparticle (LNP) Delivery Carrier-Assisted Targeted Controlled Release mRNA Vaccines in Tumor Immunity","volume":"12","author":"L Wu","year":"2024","journal-title":"Vaccines (Basel)"},{"issue":"12","key":"pcbi.1013163.ref006","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1038\/s41578-021-00358-0","article-title":"Lipid nanoparticles for mRNA delivery","volume":"6","author":"X Hou","year":"2021","journal-title":"Nat Rev Mater"},{"issue":"1","key":"pcbi.1013163.ref007","first-page":"11","article-title":"Delivery Strategies for mRNA Vaccines","volume":"36","author":"S Ramachandran","year":"2022","journal-title":"Pharmaceut Med"},{"issue":"10","key":"pcbi.1013163.ref008","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.1016\/j.immuni.2023.09.011","article-title":"The cancer-immunity cycle: Indication, genotype, and immunotype","volume":"56","author":"I Mellman","year":"2023","journal-title":"Immunity"},{"issue":"6","key":"pcbi.1013163.ref009","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1038\/s41587-022-01294-2","article-title":"The clinical progress of mRNA vaccines and immunotherapies","volume":"40","author":"AJ Barbier","year":"2022","journal-title":"Nat Biotechnol"},{"issue":"10","key":"pcbi.1013163.ref010","doi-asserted-by":"crossref","first-page":"11149","DOI":"10.1002\/cam4.5698","article-title":"Role of tumor microenvironment in cancer progression and therapeutic strategy","volume":"12","author":"Q Wang","year":"2023","journal-title":"Cancer Med"},{"issue":"1","key":"pcbi.1013163.ref011","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s12943-022-01528-6","article-title":"RNA-mediated immunotherapy regulating tumor immune microenvironment: next wave of cancer therapeutics","volume":"21","author":"PR Pandey","year":"2022","journal-title":"Mol Cancer"},{"issue":"7","key":"pcbi.1013163.ref012","doi-asserted-by":"crossref","first-page":"2969","DOI":"10.1016\/j.apsb.2022.03.011","article-title":"mRNA cancer vaccines: Advances, trends and challenges","volume":"12","author":"Q He","year":"2022","journal-title":"Acta Pharm Sin B"},{"issue":"7","key":"pcbi.1013163.ref013","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/s41571-024-00902-1","article-title":"Cancer mRNA vaccines: clinical advances and future opportunities","volume":"21","author":"EJ Sayour","year":"2024","journal-title":"Nat Rev Clin Oncol"},{"issue":"5","key":"pcbi.1013163.ref014","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nrclinonc.2018.29","article-title":"Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges","volume":"15","author":"D Fukumura","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"pcbi.1013163.ref015","doi-asserted-by":"crossref","first-page":"114301","DOI":"10.1016\/j.addr.2022.114301","article-title":"Modulating tumor physical microenvironment for fueling CAR-T cell therapy","volume":"185","author":"Z Luo","year":"2022","journal-title":"Adv Drug Deliv Rev"},{"key":"pcbi.1013163.ref016","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1146\/annurev-physiol-020518-114700","article-title":"Normalizing Function of Tumor Vessels: Progress, Opportunities, and Challenges","volume":"81","author":"JD Martin","year":"2019","journal-title":"Annu Rev Physiol"},{"issue":"1","key":"pcbi.1013163.ref017","doi-asserted-by":"crossref","first-page":"196","DOI":"10.3390\/cancers15010196","article-title":"Engineering the Tumor Immune Microenvironment through Minimally Invasive Interventions","volume":"15","author":"K Pal","year":"2022","journal-title":"Cancers (Basel)"},{"key":"pcbi.1013163.ref018","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":"E Henke","year":"2020","journal-title":"Front Mol Biosci"},{"key":"pcbi.1013163.ref019","article-title":"Modulating cancer mechanopathology to restore vascular function and enhance immunotherapy","author":"F Mpekris","year":"2024","journal-title":"Cell Reports Medicine"},{"issue":"2","key":"pcbi.1013163.ref020","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3390\/vaccines11020394","article-title":"Overcoming Suppressive Tumor Microenvironment by Vaccines in Solid Tumor","volume":"11","author":"Y-J Xie","year":"2023","journal-title":"Vaccines (Basel)"},{"key":"pcbi.1013163.ref021","doi-asserted-by":"crossref","first-page":"109367","DOI":"10.1016\/j.intimp.2022.109367","article-title":"The main battlefield of mRNA vaccine - Tumor immune microenvironment","volume":"113","author":"X Li","year":"2022","journal-title":"Int Immunopharmacol"},{"issue":"7963","key":"pcbi.1013163.ref022","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1038\/s41586-023-06063-y","article-title":"Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer","volume":"618","author":"LA Rojas","year":"2023","journal-title":"Nature"},{"issue":"5","key":"pcbi.1013163.ref023","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/s41568-025-00796-w","article-title":"Using mathematical modelling and AI to improve delivery and efficacy of therapies in cancer","volume":"25","author":"C Harkos","year":"2025","journal-title":"Nat Rev Cancer"},{"issue":"1","key":"pcbi.1013163.ref024","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.jacbts.2021.10.014","article-title":"Dynamic Multiscale Regulation of Perfusion Recovery in Experimental Peripheral Arterial Disease: A Mechanistic Computational Model","volume":"7","author":"C Zhao","year":"2022","journal-title":"JACC Basic Transl Sci"},{"issue":"9","key":"pcbi.1013163.ref025","doi-asserted-by":"crossref","first-page":"4447","DOI":"10.1073\/pnas.2001050117","article-title":"Immunoactivating the tumor microenvironment enhances immunotherapy as predicted by integrative computational model","volume":"117","author":"AS Popel","year":"2020","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"pcbi.1013163.ref026","doi-asserted-by":"crossref","first-page":"421","DOI":"10.3390\/ijms20020421","article-title":"Mechanistic Computational Models of MicroRNA-Mediated Signaling Networks in Human Diseases","volume":"20","author":"C Zhao","year":"2019","journal-title":"Int J Mol Sci"},{"key":"pcbi.1013163.ref027","doi-asserted-by":"crossref","first-page":"924","DOI":"10.3389\/fimmu.2019.00924","article-title":"Quantitative Mechanistic Modeling in Support of Pharmacological Therapeutics Development in Immuno-Oncology","volume":"10","author":"K Peskov","year":"2019","journal-title":"Front Immunol"},{"issue":"3","key":"pcbi.1013163.ref028","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2211132120","article-title":"Mechanistic model for booster doses effectiveness in healthy, cancer, and immunosuppressed patients infected with SARS-CoV-2","volume":"120","author":"C Voutouri","year":"2023","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pcbi.1013163.ref029","doi-asserted-by":"crossref","first-page":"106606","DOI":"10.1016\/j.ijantimicag.2022.106606","article-title":"Mechanistic Models of COVID-19: Insights into Disease Progression, Vaccines, and Therapeutics","volume":"60","author":"R Desikan","year":"2022","journal-title":"Int J Antimicrob Agents"},{"issue":"3","key":"pcbi.1013163.ref030","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2021642118","article-title":"In silico dynamics of COVID-19 phenotypes for optimizing clinical management","volume":"118","author":"C Voutouri","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"pcbi.1013163.ref031","doi-asserted-by":"crossref","first-page":"101436","DOI":"10.1016\/j.xcrm.2024.101436","article-title":"In silico clinical studies for optimal COVID-19 vaccination schedules in patients with cancer","volume":"5","author":"C Voutouri","year":"2024","journal-title":"Cell Rep Med"},{"issue":"5","key":"pcbi.1013163.ref032","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0301780","article-title":"Dynamic heterogeneity in COVID-19: Insights from a mathematical model","volume":"19","author":"C Voutouri","year":"2024","journal-title":"PLoS One"},{"issue":"12","key":"pcbi.1013163.ref033","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1011740","article-title":"Mathematical modeling of intratumoral immunotherapy yields strategies to improve the treatment outcomes","volume":"19","author":"C Harkos","year":"2023","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1013163.ref034","doi-asserted-by":"crossref","first-page":"111768","DOI":"10.1016\/j.jtbi.2024.111768","article-title":"Investigating the synergistic effects of immunotherapy and normalization treatment in modulating tumor microenvironment and enhancing treatment efficacy","volume":"583","author":"C Harkos","year":"2024","journal-title":"J Theor Biol"},{"issue":"1","key":"pcbi.1013163.ref035","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1005259","article-title":"A Validated Multiscale In-Silico Model for Mechano-sensitive Tumour Angiogenesis and Growth","volume":"13","author":"V Vavourakis","year":"2017","journal-title":"PLoS Comput Biol"},{"issue":"26","key":"pcbi.1013163.ref036","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2301606120","article-title":"Biodegradable lipophilic polymeric mRNA nanoparticles for ligand-free targeting of splenic dendritic cells for cancer vaccination","volume":"120","author":"E Ben-Akiva","year":"2023","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pcbi.1013163.ref037","doi-asserted-by":"crossref","first-page":"4223","DOI":"10.1038\/s41467-023-39938-9","article-title":"mRNA lipid nanoparticle-mediated pyroptosis sensitizes immunologically cold tumors to checkpoint immunotherapy","volume":"14","author":"F Li","year":"2023","journal-title":"Nat Commun"},{"issue":"6","key":"pcbi.1013163.ref038","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1080\/15384047.2020.1739484","article-title":"Cytokines secreted by stromal cells in TNBC microenvironment as potential targets for cancer therapy","volume":"21","author":"MK Malone","year":"2020","journal-title":"Cancer Biol Ther"},{"issue":"5","key":"pcbi.1013163.ref039","doi-asserted-by":"crossref","first-page":"190366","DOI":"10.1098\/rsos.190366","article-title":"In silico simulation of a clinical trial with anti-CTLA-4 and anti-PD-L1 immunotherapies in metastatic breast cancer using a systems pharmacology model","volume":"6","author":"H Wang","year":"2019","journal-title":"R Soc Open Sci"},{"issue":"2","key":"pcbi.1013163.ref040","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.ejca.2008.10.026","article-title":"New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)","volume":"45","author":"EA Eisenhauer","year":"2009","journal-title":"Eur J Cancer"},{"key":"pcbi.1013163.ref041","doi-asserted-by":"crossref","first-page":"103809","DOI":"10.1016\/j.ebiom.2021.103809","article-title":"Strategies to minimize heterogeneity and optimize clinical trials in Acute Respiratory Distress Syndrome (ARDS): Insights from mathematical modelling","volume":"75","author":"S Subudhi","year":"2022","journal-title":"EBioMedicine"},{"issue":"3","key":"pcbi.1013163.ref042","article-title":"Complex heatmap visualization","volume":"1","author":"Z Gu","year":"2022","journal-title":"Imeta"},{"key":"pcbi.1013163.ref043","article-title":"A Heatmap-Based Visualization Technique for Finding Operational Problems","volume-title":"2019 23rd International Conference in Information Visualization\u2013Part II","author":"S Yagi","year":"2019"},{"issue":"2","key":"pcbi.1013163.ref044","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0004632","article-title":"Micro-environmental mechanical stress controls tumor spheroid size and morphology by suppressing proliferation and inducing apoptosis in cancer cells","volume":"4","author":"G Cheng","year":"2009","journal-title":"PLoS One"},{"issue":"11","key":"pcbi.1013163.ref045","doi-asserted-by":"crossref","first-page":"3509","DOI":"10.1007\/s10439-010-0097-0","article-title":"Gene expression profiles in 3D tumor analogs indicate compressive strain differentially enhances metastatic potential","volume":"38","author":"ZN Demou","year":"2010","journal-title":"Ann Biomed Eng"},{"issue":"5","key":"pcbi.1013163.ref046","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1158\/0008-5472.CAN-05-2242","article-title":"Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector","volume":"66","author":"TD McKee","year":"2006","journal-title":"Cancer Res"},{"key":"pcbi.1013163.ref047","doi-asserted-by":"crossref","first-page":"0004","DOI":"10.1038\/s41551-016-0004","article-title":"Solid stress and elastic energy as measures of tumour mechanopathology","volume":"1","author":"HT Nia","year":"2016","journal-title":"Nat Biomed Eng"},{"key":"pcbi.1013163.ref048","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.nicl.2018.08.032","article-title":"Towards patient-specific modeling of brain tumor growth and formation of secondary nodes guided by DTI-MRI","volume":"20","author":"S Angeli","year":"2018","journal-title":"Neuroimage Clin"},{"key":"pcbi.1013163.ref049","doi-asserted-by":"crossref","first-page":"10","DOI":"10.3389\/fonc.2019.00010","article-title":"Computational Modeling of the Crosstalk Between Macrophage Polarization and Tumor Cell Plasticity in the Tumor Microenvironment","volume":"9","author":"X Li","year":"2019","journal-title":"Front Oncol"},{"issue":"10","key":"pcbi.1013163.ref050","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s11538-023-01201-z","article-title":"Modeling the Role of Immune Cell Conversion in the Tumor-Immune Microenvironment","volume":"85","author":"AS Moffett","year":"2023","journal-title":"Bull Math Biol"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1013163","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T00:00:00Z","timestamp":1750896000000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1013163","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T18:01:22Z","timestamp":1750960882000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1013163"}},"subtitle":[],"editor":[{"given":"Matthew","family":"Bashton","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2025,6,12]]},"references-count":50,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6,12]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1013163","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,12]]}}}