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.