STAT3 restrains dendritic cell function and tumor immunity

Abstract STAT3 is considered an oncogene in multiple human cancers. However, its direct involvement in dendritic cell (DC)-mediated antitumor immunity and immune checkpoint blockade (ICB) remains unknown. Here, we found that STAT3 was constitutively activated in DCs and restrained DC function in the tumor microenvironment (TME). Genetic ablation of STAT3 in DCs resulted in enhanced DC function and T cell immunity, thereby slowing down tumor progression in tumor bearing mouse models. Analogously, targeting STAT3 with a proteasome degradation agent, SD-36, preferentially deleted STAT3 expression in DCs, enhanced DC dependent-T cell immunity, and therapeutically synergized ICB in multiple tumor-bearing mouse models. Clinically, the combination of Stat3 expression and DC gene signature correlated with complete response in patients who received ICB. Thus, the STAT3 signaling pathway restrains DC function and targeting STAT3 has the potential to promote an immunologic TME sensitizing immunotherapy.