Figure 3.

CD44 and STAT3 support the communication between tumor cells and the tumor microenvironment (TME) to drive cancer progression/recurrence, immunosuppression, and chemoresistance. Increased CD44 and STAT3 activity in tumor cells promotes proximal cancer-associated fibroblast differentiation, which in turn further supports tumor progression through pro-tumorigenic factor secretion forming a positive feed-forward loop. In addition, CD44 in both cancer cells and CAFs facilitate the expansion and recruitment of myeloid-derived suppressor cells (MDSCs) that either directly inhibit cytotoxic effector CD8+ T cell function or drive immunoregulatory T cell (Treg) differentiation. Both CD44 and STAT3 contribute to tumor Treg expansion through upregulating FoxP3 expression. High STAT3 activation in B cells also results in immunosuppressive phenotype. At the same time, tumor-associated macrophages (TAMs) in the TME have also been shown to repress effector T cell-mediated anti-tumor immunity through immunosuppressive cytokine production and immune checkpoint expression, which requires STAT3 transcriptional activity. Moreover, increased STAT3 signaling in tumor surrounding TAMs promotes cancer stem cell phenotype, which in turn further drives immunosuppressive macrophage phenotype. Finally, CD44 and STAT3 signaling in both tumor and endothelial cells contributes to new blood vessel formation via angiogenic factor expression.