Abstract The extracellular matrix (ECM) forms a dynamic structure around cells, providing environmental cues, mechanical support, and tissue protection. It is composed of fibrous proteins, glycosaminoglycans (GAGs), proteoglycans, and glycoproteins. The molecular, physical, and mechanical properties of the ECM regulate the motility, survival, and function of immune cells. In most cancers, inflammatory cytokines and proteases—particularly matrix metalloproteinases(MMPs)—released within the immune-infiltrated inflammatory microenvironment can remodel the ECM. Cytokines such as tumor necrosis factor-α (TNF), interleukin, and transforming growth factor-beta (TGF-β) modulate the expression of various ECM molecules and promote host cell differentiation, thereby shaping a stroma conducive to tumor survival and metastasis. When ECM components become dysregulated, they act as ligands interacting with immune cell receptors, suppressing the function of specific immune cell subsets in the tumor microenvironment (TME), and activating downstream intracellular signaling pathways that are exploited by cancer cells to facilitate progression. This review systematically outlines key ECM constituents, molecular mediators of ECM remodeling, and their role in regulating immune cell behavior, including T cell exhaustion and macrophage polarization. It also elucidates the direct interactions between ECM and immune cells within inflammatory settings. Furthermore, we explore therapeutic strategies targeting ECM-mediated immunosuppression in solid tumors. This study highlights promising approaches to enhance the efficacy of cancer immunotherapy.
Zhang et al. (Fri,) studied this question.