Targeting collagen in “armored and cold” tumors: Overcoming barriers to cancer therapy

Collagen contributes to extracellular matrix formation and stiffness, providing a three-dimensional framework that supports the development and growth of solid tumors. By interacting with specific tumor cell receptors, collagen influences tumor cell signaling pathways, promoting cancer progression and drug resistance. Recent advancements in understanding the tumor extracellular matrix have underscored collagen's role in fostering an immunosuppressive tumor microenvironment (TME) and acting as a barrier to immunotherapy. Understanding the immunosuppressive mechanisms of collagen in the TME has revealed novel therapeutic targets and opportunities. This review highlights the immunoregulatory functions of collagen in the TME and provides a comprehensive overview of integrating collagen scores with traditional immunoscore-based immunotyping methods to enhance response prediction. Additionally, we discuss recent therapeutic developments in collagen targeting and their clinical potential for enhancing anti-cancer immunity.