Chemically Inducible Cyclic Dinucleotides as Self-Deliverable STING Agonists with Enhanced Antitumor Immunity

The stimulator of interferon genes (STING) has emerged as a promising therapeutic target in cancer immunotherapy. Cyclic dinucleotide (CDN)-based agonists are known to activate the STING signaling pathway; however, their clinical applications are largely hindered by challenges such as poor stability, low cell penetrability, and the lack of spatiotemporal controls that can result in off-target inflammatory responses. Here, we reported a novel design of chemically inducible CDNs (iCDNs) for efficient cellular uptake and on-demand STING activation through the installation of bio-orthogonal chemical groups onto the phosphodiester sites of CDNs. We demonstrated that iCDNs could effectively self-deliver into cells and enable bio-orthogonal activation of STING signaling via Staudinger reduction or the inverse-electron-demand Diels-Alder (IEDDA) reaction. This strategy was further extended to respond to light and endogenous enzymes, allowing for spatiotemporal and cell-specific control of STING activation. In a poorly immunogenic tumor model, the bio-orthogonal iCDNs were demonstrated to conditionally activate the STING signaling pathway upon chemical induction, with enhanced antitumor immunity and reduced systemic cytokine release in serum. We further showed that the bio-orthogonal iCDNs with a targeting moiety boosted antitumor efficacy and sensitized tumor responses to an immune checkpoint blockade (ICB). The iCDNs provide a useful strategy for the efficient delivery of CDNs and spatiotemporal control of CDN-mediated STING activation, underscoring their potential in drug development for cancer immunotherapy.