Overcoming STING-Driven Immunosuppression with a Bifunctional STING Agonist/PD-L1 Inhibitor for Enhanced Antitumor Immunity.

Activation of the stimulator of interferon gene (STING) pathway represents a highly promising therapeutic strategy for cancer immunotherapy. However, the clinical translation of STING agonist monotherapy is hindered by inconsistent efficacy and the rapid emergence of drug resistance, particularly due to STING activation-induced programmed death ligand 1 (PD-L1) upregulation, which limits its antitumor efficacy. In this study, a molecular conjugation strategy was developed that effectively mitigates STING-driven PD-L1 upregulation, thereby synergistically enhancing antitumor immune responses. The preferred candidate SMU-3k was identified, which not only potently activates the STING pathway but also blocks the PD-1/PD-L1 interaction. SMU-3k demonstrates robust and synergistic inhibition of tumor growth in the MC38 murine colon cancer model, with no evident immune-related adverse effects observed. This approach not only significantly enhances the antitumor efficacy of STING pathway activation but also provides a solid foundation for advancing the preclinical development of combination immunotherapies.