Abstract / Summary
Cancer-associated fibroblasts (CAFs) are key regulators of the tumor microenvironment (TME) and influence multiple stages of tumor metastasis through extracellular matrix (ECM) remodeling, immune modulation, angiogenesis, metabolic interactions, and pre-metastatic niche (PMN) formation. Recent advances in single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and multi-omics technologies have substantially expanded our understanding of CAF heterogeneity, revealing diverse fibroblast states with distinct molecular programs, spatial organization, and functional properties. Importantly, the relationship between CAF heterogeneity and metastatic progression is bidirectional: distinct fibroblast states can regulate specific steps of the metastatic cascade, whereas tumor-derived, inflammatory, vascular, mechanical, metabolic, and therapy-associated cues can in turn reshape CAF-state composition and function. How these reciprocal interactions determine metastatic behavior and therapeutic response remains incompletely understood. In this Review, we examine how recurrent CAF programs—including myofibroblastic, inflammatory, antigen-presentation-associated, and vascular-associated fibroblast states—interact with distinct yet interconnected steps of the metastatic cascade, including ECM remodeling, epithelial–mesenchymal transition and local invasion, immune escape, angiogenesis and vascular dissemination, pre-metastatic niche formation, and metastatic colonization. We further discuss the context-dependent tumor-promoting and tumor-restraining functions of CAFs and critically evaluate emerging therapeutic strategies, with particular emphasis on CAF plasticity, state transitions, functional reprogramming, and selective modulation rather than indiscriminate stromal depletion. By integrating cellular state, spatial niche, metastatic stage, and phenotypic plasticity, we propose a metastasis-oriented framework for understanding CAF heterogeneity and for guiding more precise stromal-targeted therapeutic strategies.