The extracellular matrix (ECM) is a critical component of tumors, providing mechanical support, influencing the microenvironment, and serving as a reservoir for signaling molecules. The abundance and cross-linking of ECM components determine tissue stiffness, which can disrupt normal mechanotransduction and promote malignant progression. Understanding ECM dysregulation in the tumor microenvironment (TME) is essential for identifying potential therapeutic targets in cancer treatment. This review summarizes the roles of ECM components, their interactions with immune cells, and the regulators of onco-immune responses. The ECM consists of proteins, glycoproteins, and polysaccharides that provide structural support and regulate cellular mechanisms. In the TME, the ECM's stiffness and composition significantly influence immune cell behavior. For example, the basement membrane (BM) plays a protective role in epithelial cancers, while the interstitial matrix (IM) is composed of collagen types I and III, elastin fibers, and glycoproteins. The stiffness of the ECM can impede immune cell migration, but immune cells can generate matrix metalloproteinases (MMPs) to degrade the ECM and facilitate migration. Collagens, the most abundant proteins in mammals, play a crucial role in maintaining tissue structure and mechanical properties. Different collagen types, such as collagen I, V, and XI, contribute to the formation and organization of collagen fibrils. Proteoglycans, including syndecans and perlecan, also play important roles in ECM composition and function. Hyaluronic acid (HA) interacts with glycoproteins like CD44 and RHAMM, influencing immune cell signaling and migration. Immune cells, including tumor-associated macrophages (TAMs), neutrophils, dendritic cells, and natural killer (NK) cells, are involved in ECM remodeling. TAMs contribute to ECM remodeling by degrading existing components and synthesizing new proteins, creating a reactive stroma that supports tumor growth. Neutrophils produce NETs that target laminin and facilitate cancer cell migration. Dendritic cells and NK cells also play roles in ECM remodeling through the expression of enzymes like heparanase. The ECM's stiffness and composition significantly influence immune cell behavior, including T cell activation, migration, and function. The orientation and density of collagen fibers affect T cell distribution and movement within the tumor stroma. ECM stiffness can promote immunosuppressive phenotypes in macrophages and T cells, hindering immune responses. The interaction between ECM components and immune cell receptors, such as DDRs and LAIRs, is crucial for regulating immune cell activation and function. Overall, the ECM plays a critical role in tumor immunity by influencing immune cell behavior, signaling, and function. Understanding the complex interactions between the ECM and immune cells is essential for developing effective cancer therapies.The extracellular matrix (ECM) is a critical component of tumors, providing mechanical support, influencing the microenvironment, and serving as a reservoir for signaling molecules. The abundance and cross-linking of ECM components determine tissue stiffness, which can disrupt normal mechanotransduction and promote malignant progression. Understanding ECM dysregulation in the tumor microenvironment (TME) is essential for identifying potential therapeutic targets in cancer treatment. This review summarizes the roles of ECM components, their interactions with immune cells, and the regulators of onco-immune responses. The ECM consists of proteins, glycoproteins, and polysaccharides that provide structural support and regulate cellular mechanisms. In the TME, the ECM's stiffness and composition significantly influence immune cell behavior. For example, the basement membrane (BM) plays a protective role in epithelial cancers, while the interstitial matrix (IM) is composed of collagen types I and III, elastin fibers, and glycoproteins. The stiffness of the ECM can impede immune cell migration, but immune cells can generate matrix metalloproteinases (MMPs) to degrade the ECM and facilitate migration. Collagens, the most abundant proteins in mammals, play a crucial role in maintaining tissue structure and mechanical properties. Different collagen types, such as collagen I, V, and XI, contribute to the formation and organization of collagen fibrils. Proteoglycans, including syndecans and perlecan, also play important roles in ECM composition and function. Hyaluronic acid (HA) interacts with glycoproteins like CD44 and RHAMM, influencing immune cell signaling and migration. Immune cells, including tumor-associated macrophages (TAMs), neutrophils, dendritic cells, and natural killer (NK) cells, are involved in ECM remodeling. TAMs contribute to ECM remodeling by degrading existing components and synthesizing new proteins, creating a reactive stroma that supports tumor growth. Neutrophils produce NETs that target laminin and facilitate cancer cell migration. Dendritic cells and NK cells also play roles in ECM remodeling through the expression of enzymes like heparanase. The ECM's stiffness and composition significantly influence immune cell behavior, including T cell activation, migration, and function. The orientation and density of collagen fibers affect T cell distribution and movement within the tumor stroma. ECM stiffness can promote immunosuppressive phenotypes in macrophages and T cells, hindering immune responses. The interaction between ECM components and immune cell receptors, such as DDRs and LAIRs, is crucial for regulating immune cell activation and function. Overall, the ECM plays a critical role in tumor immunity by influencing immune cell behavior, signaling, and function. Understanding the complex interactions between the ECM and immune cells is essential for developing effective cancer therapies.