Bidirectional communication between cells and their microenvironment has a key function in normal tissue homeostasis, and in disease initiation, progression and a patient’s prognosis, at the very least. The extracellular matrix (ECM), as an element of all tissues and cellular microenvironment, is a frequently overlooked component implicated in the pathogenesis and progression of several diseases. In the inflammatory microenvironment (IME), different alterations resulting from remodeling processes can affect ECM, progressively inducing cancer initiation and the passage toward a tumor microenvironment (TME). Indeed, it has been demonstrated that altered ECM components interact with a variety of surface receptors triggering intracellular signaling that affect cellular pathways in turn. This review aims to support the notion that the ECM and its alterations actively participate in the promotion of chronic inflammation and cancer initiation. In conclusion, some data obtained in cancer research with the employment of decellularized ECM (dECM) models are described. The reported results encourage the application of dECM models to investigate the short circuits contributing to the creation of distinct IME, thus representing a potential tool to avoid the progression toward a malignant lesion.