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

  • J Med Chem. 2026 May 14;69(9):10360-10379. doi: 10.1021/acs.jmedchem.5c03402.
Renjie Lin  1 ,  Mingze Yang  1 ,  Siying Zhi  1 ,  Zhihan Lin  1 ,  Lin Xie  1 ,  Zhangyong Hong  2 ,  Lan Huang  1 ,  Kui Cheng  1 ,  Zhipeng Chen  1
Affiliations
  • 1. Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, P. R. China.
PMID: 42017623 DOI: 10.1021/acs.jmedchem.5c03402
Abstract

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.

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