Biomarkers of mRNA Vaccine Efficacy Derived from Mechanistic Modeling of Tumor-immune Interactions
Chrysovalantis Voutouri, Lance L. Munn, Triantafyllos Stylianopoulos, Rakesh K. Jain.
Abstract
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—typically encapsulated in lipid nanoparticles (LNPs) 100–200 nm in size—enable 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.
Introduction
The promise of mRNA vaccines in oncology builds upon the success of COVID-19 mRNA vaccines, such as Moderna’s mRNA-1273 and Pfizer-BioNTech’s BNT162b2, which revolutionized the treatment of infectious diseases. These vaccines, encapsulated within lipid nanoparticles (LNPs), protect mRNA from degradation and facilitate its delivery into cells. In cancer treatment, mRNA vaccines introduce instructions for cells to produce tumor-specific antigens, thereby priming the immune system to recognize and attack cancer cells. This process leverages the Cancer-Immunity cycle, a critical framework for understanding the interactions between cancer and the immune system.
Methods:
We identified biomarkers and validated them using our model to predict mRNA vaccine efficacy, leading to a reduction in tumor growth. We identified both pre-treatment and on-treatment biomarkers.
Discussion
Our model offers a number of guidelines for improving mRNA vaccine-based therapies. First, ECM density and immune cell activity are crucial: low ECM density and high immune cell activity correlated with enhanced response probabilities, especially for combination therapies. Second, optimizing cytokine production and maximizing vaccine uptake under low ECM density conditions were associated with improved vaccine efficacy, suggesting that fine-tuning these parameters could improve outcomes.
Citation: Voutouri C, Munn LL, Stylianopoulos T, Jain RK (2025) Biomarkers of mRNA vaccine efficacy derived from mechanistic modeling of tumor-immune interactions. PLoS Comput Biol 21(6): e1013163. https://doi.org/10.1371/journal.pcbi.1013163
Editor: Matthew Bashton, Northumbria University, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
Received: January 4, 2025; Accepted: May 26, 2025; Published: June 12, 2025.
Copyright: © 2025 Voutouri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The COMSOL code is available at Zenodo (https://doi.org/10.5281/zenodo.14522916 ). All other relevant data are in the manuscript and its Supporting information files.
Funding: R.K.J.’s research was funded by the National Institutes of Health through grants R01-CA259253, R01-CA208205, R01-NS118929, U01-CA261842, U01-CA224348, and the Outstanding Investigator Award R35-CA197743. Additional support for R.K.J. was provided by the National Foundation for Cancer Research, Jane’s Trust Foundation, Niles Albright Research Foundation, and the Harvard Ludwig Cancer Center. L.L.M.’s research was supported by NIH grant R01-CA2044949. T.S.’s research was funded by the European Research Council (ERC) under the ERC-2023- ADG-101141357 grant. C.V. was supported by the Research and Innovation Foundation of Cyprus through a New Researcher Award (CULTURE/AWARD-YR/0523 B/0004). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: LLM owns equity in Bayer AG and is a consultant for SimBiosys. RKJ received consultant fees from DynamiCure, SPARC, SynDevRx; owns equity in Accurius, Enlight, Ophthotech, SynDevRx; and served on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund; and received a grant from Sanofi. Neither any reagent nor any funding from these organizations was used in this study. Other co-authors have no conflict of interests to declare.
