Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity

Focal adhesion kinase (FAK) plays a critical role in promoting immune evasion in tumors. In particular, the kinase activity of nuclear-targeted FAK in squamous cell carcinoma (SCC) cells contributes to the exhaustion of CD8(+) T cells and the recruitment of regulatory T cells (Tregs) into the tumor microenvironment. This occurs through the regulation of chemokine/cytokine and ligand-receptor networks, including the transcription of Ccl5, a key factor in this process. These alterations hinder the activity of antigen-primed cytotoxic CD8(+) T cells, allowing FAK-expressing tumors to grow. Mechanistically, nuclear FAK associates with chromatin and forms complexes with transcription factors and their upstream regulators, controlling Ccl5 expression. Notably, the immunomodulatory nuclear activities of FAK appear to be specific to cancerous squamous epithelial cells, as normal keratinocytes do not exhibit nuclear FAK. Furthermore, we demonstrate that the small-molecule FAK kinase inhibitor, VS-4718, which is in clinical development, induces Treg depletion and enhances a CD8(+) T cell-mediated anti-tumor response. These findings suggest that FAK inhibitors could stimulate immune-mediated tumor regression, offering new therapeutic PND-1186 possibilities for cancer treatment.