The extracellular matrix (ECM) consists of an intricate mesh of non-cellular elements that features structural proteins, with collagens being the most common, as well as matricellular proteins like periostin, thrombospondins, osteopontin, and SPARC (secreted protein acidic and rich in cysteine) (Giussani et al.
2019; Soliman et al.
2021). ECM remodeling is marked by alterations in these proteins’ content, activity, and crosslinking, affecting signal transduction. In many cancer tissues, this remodeling is signified by enhanced collagen production and accumulation, often with increased activity of enzymes like matrix metalloproteinases (MMPs), lysyl oxidase (LOX), lysyl oxidase-like proteins (LOXLs), and WNT1-inducible signaling pathway proteins (WISPs), among others (Sangaletti et al.
2017). These enzymes specifically target ECM components, catalyzing reactions that influence tissue stiffness and cell–matrix interactions through their distinct biochemical and physical characteristics (Long et al.
2022).
In collaboration with tumor cells, TAMs, especially M2 macrophages, help create a pro-carcinogenic environment. Triggered by signals from cancer cells or the ECM, TAMs play a crucial role in modifying the matrix, aiding in the directional movement of cancer cells (Liguori et al.
2011). They actively remodel the ECM through extensive matrix breakdown and production of ECM proteins. The lack of TAMs notably reduces the density and cross-linking of collagen, particularly diminishing the expression of collagen types I and XIV in cancer-associated fibroblasts (CAFs) (Afik et al.
2016). The assembly of the ECM is a crucial and highly controlled step in the process of tissue repair. When the group of ECM is impaired, it often results in fibrosis, a significant health concern that contributes to a high morbidity and mortality rate (Yoshimura
2024; Zhao et al.
2022). Fibrosis can affect many tissues, including the liver, kidney, lungs, heart, and skin. According to prevailing research, M1 macrophages are generally recognized as initiators of the healing process, whereas M2 macrophages are considered to facilitate the resolution of healing (Spiller and Koh
2017). In cases where the wound healing process is prolonged or does not correctly conclude, a pathological form of fibrosis, driven by Th2 responses and mediated by M2 macrophages, is commonly believed to occur (Wynn and Barron
2010).M2 macrophages promote tissue remodeling and angiogenesis within the TME, contributing to tumor progression ( Liu et al.
2022). They can remodel the TME through interactions with other cells, impacting their number, activity, and phenotype associated with drug resistance (Wang, et al.
2021). M2 macrophages express MARCO, which triggers a sequential remodeling of the endothelium-interstitial matrix, forming a pre-metastatic niche in the microfluidic TME (Cendrowicz et al.
2021). M2 macrophages also express enzymes such as MMP-2, MMP-7, MMP-9, MMP-11, MMP-12, and cyclooxygenase-2, which are involved in matrix remodeling and regulation of angiogenesis (Egawa et al.
2013; Hao et al.
2017; Lin et al.
2021). The secretion of MMPs from M2 macrophages, particularly the high expression of MMP-11, plays a crucial role in facilitating cancer cell metastasis, with an overexpression of MMP-11 in M2 macrophages (Saeidi et al.
2023; Zhang et al.
2016). This overexpression increases monocyte recruitment and promotes the migration of HER2 + breast cancer cells through the CCL2/CCR2/MAPK pathway, underscoring the significant impact of TAM-derived MMP-11 on the progression and metastatic potential of breast cancer (Kang et al.
2022).