Targets in the Tumour Matrisome to Promote Cancer Therapy Response

Simple Summary The extracellular matrix acts as scaffolding to support the structure and function of the cells in our body. In cancer, this matrix is altered in a way that helps cancer cells to grow, spread and avoid the immune system. The altered matrix can also prevent cancer treatments like chemotherapy and immunotherapy from working. Targeting the matrix with drugs is emerging as an exciting way to modify the scaffold in a precise way to improve the effectiveness of cancer treatments in patients. In this review, we will examine strategies to target the matrix with drugs, which can help the immune system fight cancer and improve the response to existing cancer therapies.Abstract The extracellular matrix (ECM) is composed of complex fibrillar proteins, proteoglycans, and macromolecules, generated by stromal, immune, and cancer cells. The components and organisation of the matrix evolves as tumours progress to invasive disease and metastasis. In many solid tumours, dense fibrotic ECM has been hypothesised to impede therapy response by limiting drug and immune cell access. Interventions to target individual components of the ECM, collectively termed the matrisome, have, however, revealed complex tumour-suppressor, tumour-promoter, and immune-modulatory functions, which have complicated clinical translation. The degree to which distinct components of the matrisome can dictate tumour phenotypes and response to therapy is the subject of intense study. A primary aim is to identify therapeutic opportunities within the matrisome, which might support a better response to existing therapies. Many matrix signatures have been developed which can predict prognosis, immune cell content, and immunotherapy responses. In this review, we will examine key components of the matrisome which have been associated with advanced tumours and therapy resistance. We have primarily focussed here on targeting matrisome components, rather than specific cell types, although several examples are described where cells of origin can dramatically affect tumour roles for matrix components. As we unravel the complex biochemical, biophysical, and intracellular transduction mechanisms associated with the ECM, numerous therapeutic opportunities will be identified to modify tumour progression and therapy response.