The extracellular matrix – immune microenvironment crosstalk in cancer therapy: Challenges and opportunities

Targeting the tumour immune microenvironment (TIME) by cancer immunotherapy has led to improved patient outcomes. However, response to these treatments is heterogeneous and cancer-type dependant. The therapeutic activity of classical cancer therapies such as chemotherapy, radiotherapy, and surgical oncology is modulated by alterations of the TIME. A major regulator of immune cell function and resistance to both immune and classical therapies is the extracellular matrix (ECM). Concurrently, cancer therapies reshape the TIME as well as the ECM, causing both pro- and anti-tumour responses. Accordingly, the TIME-ECM crosstalk presents attractive opportunities to improve therapy outcomes. Here, we review the molecular crosstalk between the TIME and the ECM in cancer and its implications in cancer progression and clinical intervention. Additionally, we discuss examples and future directions of ECM and TIME co-targeting in combination with oncological therapies including surgery, chemotherapy, and radiotherapy.