Tumor Plasticity and Microenvironmental Crosstalk as Drivers of Metastasis and Therapy Resistance

ABSTRACT Metastasis remains the leading cause of cancer‐related mortality and is increasingly recognized as a consequence of dynamic interactions between tumor cell plasticity and a heterogeneous tumor microenvironment (TME). Rather than being genetically fixed, cancer cells exhibit phenotypic flexibility, enabling reversible transitions among epithelial, mesenchymal, and stem‐like states in response to intrinsic programs and extrinsic microenvironmental cues, central to this adaptability. This review synthesizes emerging evidence that tumor progression is governed by reciprocal feedback loops between plastic tumor cells and distinct microenvironmental niches, including hypoxic cores, invasive margins, and perivascular regions. We highlight how stromal components, immune infiltrates, endothelial cells, and extracellular matrix (ECM) remodeling dynamically shape tumor cell states through biochemical and biophysical signals. Advances in single‐cell and spatial transcriptomic technologies have revealed the spatial organization and reversibility of these plastic phenotypes, uncovering rare but clinically significant drug‐tolerant persister populations. Importantly, we discuss plasticity‐mediated therapy resistance as an adaptive, nongenetic process driven by transcriptional and epigenetic reprogramming, metabolic flexibility, ECM stiffening–induced mechanotransduction, and immune‐checkpoint plasticity under therapeutic pressure. Together, these findings establish tumor plasticity and microenvironmental heterogeneity as an integrated, evolving system that fuels metastasis and limits durable treatment responses. Targeting this tumor–TME plasticity axis represents a promising strategy to disrupt metastatic progression and overcome therapeutic resistance.