Anticancer flavonoids are mouse-selective STING agonists.

Area of Science:

• Immunology
• Pharmacology
• Molecular Biology

Background:

• Flavonoids FAA and DMXAA demonstrated significant antitumor activity in mice but failed in clinical trials.
• These compounds trigger cytokine release from leukocytes, leading to tumor-specific vascular damage and other antitumor effects via an unknown molecular target.
• The mechanism involves interaction with the stimulator of interferon genes (STING) pathway.

Discussion:

• DMXAA acts as a competitive agonist ligand for mouse STING, a receptor for cyclic-di-GMP (c-di-GMP) and cyclic-GMP-AMP.
• Structure-activity relationship studies show a correlation between STING binding affinity, pathway activation, and antitumor efficacy in mice.
• The lack of binding to human STING explains the inefficacy and toxicity observed in clinical trials.

Key Insights:

• STING is identified as the molecular target mediating the antitumor effects of FAA and DMXAA in mice.
• Flavonoid binding to STING activates innate immune responses crucial for tumor suppression.
• Species-specific differences in STING interaction are critical for therapeutic translation.

Outlook:

• STING represents a druggable target for novel chemotherapy strategies.
• Targeting STING could lead to new treatments that harness innate immune activation for cancer therapy.
• Further research into human STING agonists is warranted for clinical development.