Model depicting the role of OPN in tumor immune microenvironment (TIME): (A) Role of OPN in shaping immunosuppressive TME: tumor-derived OPN activates stromal cells by trans-differentiation of fibroblasts to myofibroblasts, resulting in expansion of tumor. OPN-regulated PD-1/PDL1 interaction inhibits T-cell activation. Further, tumor cells downregulate the expression of IRF8, resulting in overexpression of OPN, thus leading to T-cell suppression. OPN, via the NF-κB pathway, upregulates PD-L1 expression, aiding in immune therapy escape. OPN induces the polarization of macrophages and the recruitment of monocytes. It activates TAM, leading to angiogenesis, metastasis and enrichment of CSCs via upregulation of various tumor-promoting factors such as MMP-9, N-cadherin, vimentin, ICAM-1, COX-2, PGE-2, VEGF, Sox-2, Oct-3/4, Nanog and ALDH. The polarity ratio of CXCL9 and OPN (SPP1) determines the anti- and pro-tumorigenic properties of TAMs. (B) Involvement of OPN in tumor immunity continuum: OPN is primarily associated with inflamed and immune-excluded tumors, whereas its role in immune-desert tumor remains elusive. (C) Schematic representations to identify OPN-regulated immune cell heterogeneity in cancer: OPN-regulated immune modulatory genes may be identified in TIME by CRISPR technology in breast cancer using scRNA-seq based platform
