Hot and Cold Fibrosis: The Role of Serum Biomarkers to assess the Immune Mechanisms and ECM-Cell Interactions in Human Fibrosis

Fibrosis is a pathological condition characterized by excessive accumulation of extracellular matrix (ECM) components, particularly collagens, leading to tissue scarring and organ dysfunction. In fibrosis, an imbalance between collagen synthesis (fibrogenesis) and degradation (fibrolysis) results in the deposition of fibrillar collagens disrupting the structural integrity of the ECM and, consequently, the tissue architecture. Fibrosis is associated with a wide range of chronic diseases, including liver cirrhosis, kidney fibrosis, pulmonary fibrosis, and autoimmune diseases. Recently, the concept of "hot" and "cold" fibrosis has emerged, referring to the immune status within fibrotic tissues and the nature of fibrogenic signaling. Hot fibrosis is characterized by active immune cell infiltration and inflammation, while cold fibrosis is associated with auto- and paracrine myofibroblast activation, immune cell exclusion and quiescence.This article aims to explore the relationship between hot and cold fibrosis, the role of various types of collagens and their biologically active fragments in modulating the immune system, and how serological ECM biomarkers can help the understanding of the disease-relevant interactions between immune and mesenchymal cells in fibrotic tissues. Additionally, we draw lessons from immuno-oncology research in solid tumors to shed light on potential strategies for fibrosis treatment and highlight the advantage of having a “hot fibrotic environment” to treat fibrosis by enhancing collagen degradation through modulation of the immune system.