Strategies for Efficient Targeting of Tumor Collagen for Cancer Therapy

Simple Summary The tumor microenvironment encompasses the cellular and extracellular matrix components that support and shape the three-dimensional framework in which solid tumors develop and grow. The extracellular matrix of the tumor is characterized by increased deposition and aberrant architecture of collagen fibers. Therefore, as a key mechanical component of the tumor microenvironment, collagen plays a critical role in cancer progression, metastasis, and therapeutic response. To boost the efficacy of current anticancer therapies, including immunotherapy, innovative approaches should take into account strategies directed against the dysregulated non-cancer cell stromal components. In the current review, we provide an overview of the principal approaches to target tumor collagen to provide therapeutic benefits. The tumor stroma, which comprises stromal cells and non-cellular elements, is a critical component of the tumor microenvironment (TME). The dynamic interactions between the tumor cells and the stroma may promote tumor progression and metastasis and dictate resistance to established cancer therapies. Therefore, novel antitumor approaches should combine anticancer and anti-stroma strategies targeting dysregulated tumor extracellular matrix (ECM). ECM remodeling is a hallmark of solid tumors, leading to extensive biochemical and biomechanical changes, affecting cell signaling and tumor tissue three-dimensional architecture. Increased deposition of fibrillar collagen is the most distinctive alteration of the tumor ECM. Consequently, several anticancer therapeutic strategies have been developed to reduce excessive tumor collagen deposition. Herein, we provide an overview of the current advances and challenges of the main approaches aiming at tumor collagen normalization, which include targeted anticancer drug delivery, promotion of degradation, modulation of structure and biosynthesis of collagen, and targeting cancer-associated fibroblasts, which are the major extracellular matrix producers.