PI: Karl Wittrup, Department of Chemical Engineering, MIT
We will mimic a major mechanism of innate immunity that occurs in “hot” tumors, namely the stimulator of interferon gene (STING) pathway. The STING protein resides on the membrane of the endoplasmic reticulum and is naturally activated by cytosolic cyclic dinucleotides (CDNs) synthesized by bacterial pathogens or by the endogenous cytosolic DNA sensor cGAS. Activation of STING potently induces type I IFN production, causing dendritic cell maturation and subsequent adaptive immune events. Delivery of STING agonists to the tumor microenvironment by intratumoral injection has been shown to effectively generate anti-tumor adaptive immunity, however systemic delivery is ineffective -- leaving occult metastases untreated. We will further this field by engineering (A) CDN cytosolic delivery agents, and (B) novel small protein agonists of STING.