Peptide Coacervates Promote Cytosolic Delivery of STING Agonists for Cancer Immunotherapy.

Background/

Objectives

Cyclic dinucleotide stimulator of interferon genes (STING) agonists have emerged as potential agents in cancer immunotherapy, but their clinical applications are limited by relatively poor pharmacokinetic properties.

Methods

A luciferase reporter assay was employed to screen delivery peptides capable of promoting cellular activating effect of cyclic dinucleotide STING agonists. The potent candidates were further confirmed by enzyme-linked immunosorbent assay (ELISA), real-time quantitative PCR (qPCR) and Western blotting analysis. Colon and melanoma cancer mouse models were used to examine the antitumor efficacy of the delivery peptides with cyclic GMP-AMP (cGAMP) as a therapeutic agents or vaccine adjuvant.

Results

We identify a class of STING agonist delivery peptides that efficiently facilitate cytosolic delivery of cyclic dinucleotide STING agonists and promote STING activation by forming peptide coacervates. Intratumoral administration of Sti3-4A and cGAMP effectively suppressed tumor growth and promoted antitumor immune response. Furthermore, the conjugation of tumor-specific antigen peptides with Sti3-4A promoted cytosolic co-delivery of antigen peptides and cGAMP, thus significantly boosting APC maturation, antigen cross-presentation, and T cell responses to peptide antigens. Prophylactic and therapeutic immunization with the conjugated peptides and cGAMP inhibited tumor growth in multiple murine tumor models.

Conclusion

These findings establish STING agonist delivery peptides as a versatile platform for cancer immunotherapy.