Intratumoral treatment of APT-STAT3-9R led to a reduction in the population of MDSCs and TAMs, while increasing infiltration of cytotoxic T lymphocytes in the TME. Moreover, combination therapy with APT-STAT3-9R and an anti-PD-1 antibody enhanced significant suppression of tumor growth by decreasing infiltration of these immunosuppressive immune cells while increasing the infiltration and cytotoxicity of CD8+ T cells. These findings suggest that combined blockade of STAT3 and PD-1 signaling pathways may be an effective treatment option for overcoming poor therapeutic outcomes associated with drug-resistant BRAF-mutant melanoma.