Fig. 2

Multiple roles of the extracellular matrix (ECM) in modulating the cancer-immunity cycle. The cancer-immunity cycle progresses through tumor cell death and release of tumor antigens, tumor antigen presentation, priming and activation of T cells, trafficking of T cells, T-cell infiltration of tumor and recognition of tumor cells by effectors. Matrix remodeling shapes the inflamed immune microenvironment and plays a vital role at each step of the cancer-immunity cycle. Tumor antigen presentation and generation of the adaptive immune response depends on tumor-infiltrating Batf3-cDCs, matrikines, cytokines and chemokines of CCL and CXCL family. Versikine promotes differentiation of the potent immune-stimulator Batf3-cDCs. STING pathway activation, elicited by tumor cell-derived DNA, results in type I interferon (IFN) production and DC maturation. Endothelial cells, adhesion molecules and chemokines modulate trafficking of leukocytes. Stromal cells, including endothelial cells, pericytes and CAFs, and extracellular matrix components including collagens, GPs, GAGs and PGs, regulate infiltration and polarization of immune cells. Matrikines, cytokines and laminins regulate priming and activation of T cells. Matrix proteases and matrikines, including versikine, exert direct effects on immune cell polarization and activation. ICIs block immune checkpoints to induce anti-tumor immunity; however, the tumor matrix regulates generation and proliferation of the sustained host immune response. Matrix-derived immune biomarkers promise an innovative approach to predict response to novel immunotherapies. Abbreviations: Batf3-cDCs; Batf3-dependent classical dendritic cells, IRF8; interferon regulatory factor 8, IFN; interferon, STING; stimulator of interferon genes, CAFs; cancer-associated fibroblasts, GPs; glycoproteins, GAGs; glycosaminoglycans, PGs; proteoglycans, VCAN; versican, DCs; dendritic cells, APCs; antigen presenting cells