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Mechanobiology

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

AUTHORS

Wang-Bishop LLihong , Kimmel BRBlaise R , Ngwa VMVerra M , Madden MZMatthew Z , Baljon JJJessalyn J , Florian DCDavid C , Hanna AAnn , Pastora LELucinda E , Sheehy TLTaylor L , Kwiatkowski AJAlexander J , Wehbe MMohamed , Wen XXiaona , Becker KWKyle W , Garland KMKyle M , Schulman JAJacob A , Shae DDaniel , Edwards DDeanna , Wolf MMMelissa M , Delapp RRossane , Christov PPPlamen P , Beckermann KEKathryn E , Balko JMJustin M , Rathmell WKW Kimryn , Rathmell JCJeffrey C , Chen JJin , Wilson JTJohn T . Science immunology. 2023 05 05; 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.