Intratumoral heterogeneity is a negative prognostic factor for cancer and commonly attributed to microenvironment-driven genetic mutations and/or the emergence of cancer stem-like cells. How aberrant extracellular matrix (ECM) remodeling regulates the phenotypic diversity of tumor cells, however, remains poorly understood due in part to a lack of model systems that allow isolating the physicochemical heterogeneity of malignancy-associated ECM for mechanistic studies. Here, we review the compositional, microarchitectural, and mechanical hallmarks of cancer-associated ECM and highlight biomaterials and engineering approaches to recapitulate these properties for in vitro and in vivo studies. Subsequently, we describe how such engineered platforms may be explored to define the spatiotemporal dynamics through which cancer-associated ECM remodeling regulates intratumoral heterogeneity and the cancer stem-like cell phenotype. Finally, we highlight future opportunities and technological advances to further elucidate the relationship between tumor-associated ECM dynamics and intratumoral heterogeneity.

肿瘤内异质性是癌症的负面预后因素，通常归因于微环境驱动的基因突变和/或癌症干细胞样细胞的出现。然而，异常细胞外基质 (ECM) 重塑如何调节肿瘤细胞的表型多样性仍然知之甚少，部分原因是缺乏允许分离恶性肿瘤相关 ECM 的物理化学异质性以进行机制研究的模型系统。在这里，我们回顾了癌症相关 ECM 的组成、微架构和机械特征，并强调了生物材料和工程方法，以在体外和体内概括这些特性学习。随后，我们描述了如何探索此类工程平台以定义癌症相关 ECM 重塑调节肿瘤内异质性和癌症干细胞样细胞表型的时空动态。最后，我们强调未来的机会和技术进步，以进一步阐明肿瘤相关的 ECM 动力学和肿瘤内异质性之间的关系。