The extracellular matrix (ECM) is a complex network of proteins, proteoglycans, and other molecules that regulate cell behavior, including proliferation, migration, and differentiation. In cancer, the ECM becomes dysregulated, rigid, and fibrotic, playing both pro-tumorigenic and anti-tumorigenic roles. Tumor desmoplasia, characterized by the accumulation of α-smooth muscle actin-positive fibroblasts and the deposition of a stiff ECM containing collagen, fibronectin, proteoglycans, and hyaluronic acid, is common in many solid tumors. The matrisome, the entire ensemble of genes encoding ECM-associated proteins, is crucial in cancer progression, with its components influencing tumor development, metastasis, and response to therapy. ECM stiffness is a key factor in cancer progression, with increased stiffness correlating with poor clinical outcomes and resistance to therapy. ECM remodeling in tumors leads to the formation of bioactive fragments (matricryptins or matrikines) with pro-tumor features and facilitates tumor proliferation, invasion, and metastasis. Desmoplasia promotes tumor survival, resistance to therapy, and immune escape, and may even favor tumor development before onset. The ECM's stiffness and composition are influenced by various factors, including inflammation, TGFβ, IL-6, and TNFα, which drive ECM remodeling and tumor progression. Post-transcriptional modifications of ECM components also play a critical role in cancer progression, affecting matrix stiffness, cell adhesion, and signaling pathways. The tumor microenvironment (TME) is influenced by the ECM, with mechanical forces and stiffness modulating cell behavior and tumor growth. Targeting mechanotransduction pathways, such as those involving DDR1, PIEZO1, and TRPV4, is a promising approach for cancer therapy. Inhibiting ECM stiffness through drugs like tetrathiomolybdate, halofuginone, and pirfenidon, or using CAR-T cells to deplete cancer-associated fibroblasts, may improve tumor treatment outcomes. The dynamic interplay between the ECM, stromal cells, and tumor cells creates a feedback loop that influences cancer progression, highlighting the importance of targeting the ECM in cancer therapy.The extracellular matrix (ECM) is a complex network of proteins, proteoglycans, and other molecules that regulate cell behavior, including proliferation, migration, and differentiation. In cancer, the ECM becomes dysregulated, rigid, and fibrotic, playing both pro-tumorigenic and anti-tumorigenic roles. Tumor desmoplasia, characterized by the accumulation of α-smooth muscle actin-positive fibroblasts and the deposition of a stiff ECM containing collagen, fibronectin, proteoglycans, and hyaluronic acid, is common in many solid tumors. The matrisome, the entire ensemble of genes encoding ECM-associated proteins, is crucial in cancer progression, with its components influencing tumor development, metastasis, and response to therapy. ECM stiffness is a key factor in cancer progression, with increased stiffness correlating with poor clinical outcomes and resistance to therapy. ECM remodeling in tumors leads to the formation of bioactive fragments (matricryptins or matrikines) with pro-tumor features and facilitates tumor proliferation, invasion, and metastasis. Desmoplasia promotes tumor survival, resistance to therapy, and immune escape, and may even favor tumor development before onset. The ECM's stiffness and composition are influenced by various factors, including inflammation, TGFβ, IL-6, and TNFα, which drive ECM remodeling and tumor progression. Post-transcriptional modifications of ECM components also play a critical role in cancer progression, affecting matrix stiffness, cell adhesion, and signaling pathways. The tumor microenvironment (TME) is influenced by the ECM, with mechanical forces and stiffness modulating cell behavior and tumor growth. Targeting mechanotransduction pathways, such as those involving DDR1, PIEZO1, and TRPV4, is a promising approach for cancer therapy. Inhibiting ECM stiffness through drugs like tetrathiomolybdate, halofuginone, and pirfenidon, or using CAR-T cells to deplete cancer-associated fibroblasts, may improve tumor treatment outcomes. The dynamic interplay between the ECM, stromal cells, and tumor cells creates a feedback loop that influences cancer progression, highlighting the importance of targeting the ECM in cancer therapy.