Reconstructing the Tumor Mechanical Microenvironment in Organoids: From Mechanical Cues to Biomimetic Modeling and Therapeutic Insights.

The tumor mechanical microenvironment (TMME) is a critical regulator of cancer initiation, progression, metastasis, and therapeutic response. Beyond biochemical signaling, physical cues such as matrix stiffness, solid stress, interstitial fluid flow, and extracellular matrix (ECM) architecture regulate tumor-cell behavior, stromal remodeling, abnormal vascular proliferation and leakage, immune interactions, and drug resistance. However, conventional in vitro and in vivo models remain limited in recapitulating the dynamic, heterogeneous, and coupled mechanical features of native tumors. Tumor organoids, particularly patient-derived tumor organoids (PDOs), have emerged as physiologically relevant and experimentally tractable platforms for modeling tumor mechanics, as they preserve key aspects of tumor architecture, cellular heterogeneity, and genetic background while enabling precise experimental manipulation and high-throughput analysis. This review summarizes recent advances in modeling the TMME in tumor organoids. We first discuss major mechanical features of the tumor microenvironment (TME). We then discuss current strategies for recreating these features in organoid models, including stiffness-defined matrices, engineered ECMs, microfluidic platforms, mechanical actuation systems, multicellular co-culture models, and three-dimensional (3D) bioprinting. We also highlight their applications in mechanistic studies, disease modeling, and drug testing. Finally, we discuss current limitations including the overemphasis on stiffness-based design, limited reproducibility and standardization, and insufficient preservation of tumor spatial heterogeneity and mechanical gradients. We further outline future directions toward controllable, standardized, and patient-specific organoid platforms through advances in engineered matrices, microfluidics, automation, and computational analysis. By shifting from single-parameter modeling to systems-level reconstruction of the TMME, tumor organoid models are becoming increasingly powerful platforms for mechanistic discovery and therapeutic evaluation.