The interplay between extracellular matrix remodeling and cellular lipid metabolic reprogramming in cancer: a review

Tumor-associated extracellular matrix (ECM) remodeling provides a supportive microenvironment for aberrant cellular behaviors and fate, resulting in tumor progression. Concurrently, reprogrammed lipid metabolism, characterized by dysregulated de novo lipogenesis, fatty acid oxidation (FAO), and lipid peroxidation, serves as a metabolic hallmark of cancer. Emerging evidence reveals a bidirectional crosstalk between ECM remodeling and lipid metabolic rewiring, which collectively drive tumorigenesis, survival, metastasis, and drug resistance. However, the mechanistic links connecting ECM dynamics to cellular lipid metabolism remain incompletely elucidated. In this review, we dissect the mechanistic underpinnings of ECM-lipid metabolism crosstalk, focusing on biochemical and biophysical modulation. In general, ECM-lipid metabolism axis form a self-amplifying feedback circuit, wherein ECM remodeling regulates lipid anabolism and catabolism to fuel energy production, membrane biosynthesis, and signaling molecules generation, while lipid metabolites reciprocally promote ECM degradation or deposition. Targeting critical nodes within this circuit-such as ECM-derived cues (e.g., collagen) or intracellular lipid metabolism pathway (e.g., FAO)-represents a promising strategy to disrupt tumor-stroma coevolution and enhance therapeutic efficacy. Notably, this crosstalk is not static but highly dynamic, exhibiting context-dependent dual roles influenced by variables such as cell state, cancer type, tumor site, and disease stage.