Quantitative calibration of a spatial QSP model identifies fibroblast impact on HCC immunotherapy

作者：Shuming Zhang, Hanwen Wang, Yeonju Cho, Heber L. Rocha, W. Wei‐Lynn Wong, Mark Yarchoan, Elizabeth M. Jaffee, Won Jin Ho, Luciane T. Kagohara, Elana J. Fertig, Aleksander S. Popel, Atul Deshpande · 发表于：Proceedings of the National Academy of Sciences · 年份：2026 · DOI：10.1073/pnas.2525799123 · 被引用次数：2 · 研究领域：Mathematical Biology Tumor Growth、Cancer Genomics and Diagnostics、Cancer Immunotherapy and Biomarkers

Abstract Computational models are increasingly used to predict treatment response and optimize cancer therapy strategies. Among these, quantitative systems pharmacology (QSP) models mechanistically simulate tumor progression and pharmacological interventions, enabling virtual clinical trials, model-informed drug development, and biomarker identification. Coupling QSP with an agent-based model yields a spatial QSP (spQSP) platform that captures tissue-level spatial organization of the tumor microenvironment (TME). However, parameterizing such models to represent tumor biology remains an open problem. In this study, we developed a calibration framework using the Approximate Bayesian Computation - Sequential Monte Carlo (ABC-SMC) approach to calibrate the spQSP model with a combination of clinical and spatial molecular data, reflecting the TME characteristics of human tumors. This calibration framework matches tumor architectures between spQSP model predictions and patient spatial molecular data by fitting statistical summaries of cellular neighborhoods. We demonstrate that model calibration using CODEX data from untreated HCC patients enables prediction of TME spatial molecular states in an independent cohort receiving immune-checkpoint inhibitor (ICI) and tyrosine kinase inhibitor (TKI) combination therapy. Finally, we identify spatial and non-spatial pretreatment biomarkers and assess their predictive power for therapeutic response. This workflow demonstrates how integrating ...