Engineering ECM-mimetic scaffolds from biological macromolecules for physiologically relevant tumoroid models

The tumor extracellular matrix (ECM) is a dynamic, tissue-specific network of structural proteins, adhesive glycoproteins, and glycosaminoglycans that governs cancer cell behaviour, mechanotransduction, invasion, and therapeutic response. While conventional 2D models fail to reproduce these cues, cell-based 3D tumoroids, mainly derived from cancer cell lines or patient biopsies, have advanced preclinical modelling by restoring aspects of tumor heterogeneity and biochemical gradients. However, their stability, architecture, and predictive value remain limited in the absence of ECM-mimetic scaffolds. This review synthesizes current knowledge on tumor ECM macromolecules as modular design elements, detailing how their biochemical interactions and mechanical roles can be leveraged to engineer physiologically relevant scaffolds. We evaluate major classes of ECM-mimetic platforms, including decellularized matrices, biological macromolecule-based hydrogels, synthetic and hybrid polymer networks, and commercially available systems. We examine fabrication strategies that enable tunable control over stiffness, architecture, and degradation. A materials-centered analytical framework is presented to link scaffold composition, porosity, viscoelasticity, swelling behaviour, and degradability to key tumor phenotypes, including EMT, hypoxia gradients, and drug response. By integrating stiffness landscapes from diverse tissues, we propose tumor-type-specific design maps to guide rational material selection for various cancers. We conclude by outlining the critical materials challenges that must be addressed to advance translational 3D tumor models, including the development of chemically defined scaffolds, integration with microfluidic platforms, high-throughput fabrication, and standardization for reproducible clinical application. Together, these insights position ECM-mimetic biomaterials not merely as culture supports but as engineered microenvironments essential for next-generation mechanistic studies and precision oncology.