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Molecular Design and Synthesis Center

STING-activating nanoparticles normalize the vascular-immune interface to potentiate cancer immunotherapy

AUTHORS

Wang-Bishop L , Kimmel BR , Ngwa VM , Madden MZ , Baljon JJ , Florian DC , Hanna A , Pastora LE , Sheehy TL , Kwiatkowski AJ , Wehbe M , Wen X , Becker KW , Garland KM , Schulman JA , Shae D , Edwards D , Wolf MM , Delapp R , Christov PP , Beckermann KE , Balko JM , Rathmell WK , Rathmell JC , Chen J , Wilson JT , . Science immunology. 2023 5 5; 8(83). eadd1153

ABSTRACT

The tumor-associated vasculature imposes major structural and biochemical barriers to the infiltration of effector T cells and effective tumor control. Correlations between stimulator of interferon genes (STING) pathway activation and spontaneous T cell infiltration in human cancers led us to evaluate the effect of STING-activating nanoparticles (STANs), which are a polymersome-based platform for the delivery of a cyclic dinucleotide STING agonist, on the tumor vasculature and attendant effects on T cell infiltration and antitumor function. In multiple mouse tumor models, intravenous administration of STANs promoted vascular normalization, evidenced by improved vascular integrity, reduced tumor hypoxia, and increased endothelial cell expression of T cell adhesion molecules. STAN-mediated vascular reprogramming enhanced the infiltration, proliferation, and function of antitumor T cells and potentiated the response to immune checkpoint inhibitors and adoptive T cell therapy. We present STANs as a multimodal platform that activates and normalizes the tumor microenvironment to enhance T cell infiltration and function and augments responses to immunotherapy.

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