Activating the stimulator of interferon genes (STING) signaling pathway has shown great promise in cancer immunotherapy. While most existing approaches have focused on the encapsulation of the STING agonist cyclic GMP-AMP (cGAMP) into lipid nanoparticles or polymersomes for cellular delivery, this assumes the presence of fully functional STING protein in the cells. STING signaling in several types of cancer cells has been shown to be impaired by epigenetic silencing of STING expression. Furthermore, it is still under debate whether the 19% human population carrying the HAQ STING mutation (R71H-G230A-R293Q) is fully responsive to agonist-only administrations. We discovered that the recombinant STING protein without the transmembrane domain (STINGΔTM) could be used as a functional carrier for cGAMP delivery and elicit type I IFN expression in STING-deficient cell lines. cGAMP and STINGΔTM self-assembles into a well-defined tetrameric structure with a desirable size for lymphatic accumulation. With the cGAMP-STINGΔTM complex, we generated anti-tumoral immunity in mouse melanoma and colon cancer models, providing a potential translatable platform for STING agonist-based immunotherapy.

Engineering the STING protein for cancer vaccine and treatment

ACS Spring 2022

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