A Multi-Threshold Micelle Improves Tumor Accumulation and STING Immunotherapy.

Area of Science:

• Immunology
• Nanotechnology
• Oncology

Background:

• Stimulator of interferon genes (STING) is crucial for innate immunity and anti-cancer responses.
• Current STING activators like PC7A micelles are limited to local delivery and not optimized for intravenous administration.
• Improving systemic delivery of STING agonists is essential for effective cancer immunotherapy.

Purpose of the Study:

• To engineer a novel hybrid micelle (HySTING) for improved systemic delivery and enhanced STING immunotherapy efficacy.
• To investigate the pH-sensitivity and pharmacological properties of HySTING variants.
• To evaluate the biodistribution, tumor accumulation, and anti-cancer effects of HySTING in vivo.

Main Methods:

• Designed hybrid micelles (HySTING) using PEG-b-PC7A and a secondary polymer with varying pKa values for multi-threshold pH-sensitivity.
• Assessed micelle stability, STING activation, and membrane-destabilization in relevant cell models.
• Evaluated pharmacokinetic profiles, blood circulation half-life, and tumor accumulation in mice after intravenous administration.
• Screened cyclic dinucleotides (CDNs) for improved micelle encapsulation and stability.
• Tested HySTING efficacy in a CT26 murine colon carcinoma model, including combination therapy with anti-PD-1 antibodies.

Main Results:

• HySTING variants demonstrated stepwise ultra-pH-sensitivity, maintaining PC7A's pharmacological properties.
• Intravenous administration of HySTING significantly improved blood circulation half-life (up to 18 hours) compared to PC7A (<1 hour).
• HySTING formulations showed substantially higher tumor accumulation (up to 17-fold increase).
• Identified HySTING IACS-8803 formulation with superior tumor growth inhibition and synergy with αPD-1 therapy.
• Thiol substitutions in CDN linkers enhanced micelle encapsulation and stability.

Conclusions:

• The multi-threshold pH-sensitivity of HySTING enables improved tumor biodistribution and enhanced efficacy for intravenous STING immunotherapy.
• HySTING represents a promising platform for systemic delivery of STING agonists, offering a new strategy for cancer treatment.
• Further development of HySTING formulations holds potential for overcoming limitations of current localized immunotherapies.