945 A molecularly defined polymeric platform for environmentally responsive activation of STING to enhance cancer immunotherapy
Year: 2026
Type: conference-abstract
Abstract: Background The stimulator of interferon genes (STING) pathway is a promising immuno-oncology target; however, clinical trials with STING agonists have yielded disappointing results due to poor pharmacokinetics, limited tumor accumulation, and off-target toxicity. Dimeric amidobenzimidazole (diABZI) compounds are a potent class of synthetic STING agonists under clinical investigation, but suffer from a short circulation half-life and suboptimal tumor and lymphoid tissue accumulation upon intravenous administration. To maximize its potential, we have formulated a potent diABZI analog into a a next-generation polymeric carriers to enhance drug delivery to the tumor microenvironment (TME) and augment antitumor efficacy.Methods We synthesized a diABZI-functionalized reversible addition–fragmentation chain-transfer (RAFT) polymerization agent connected via a disulfide linker to exploit high local levels of glutathione in the TME and leveraged this to create a well-defined N,N-dimethylacrylamide (DMA)-based polymer-drug conjugate (diABZI-SS-DMA). We confirmed reduction-responsive release of the active diABZI analog (diABZI-SH) and its activity in vitro. Tissue biodistribution of fluorescently labeled diABZI-SS-DMA was quantified by intravital imaging and cell-specific tumor uptake in the MC38 colorectal cancer model was assessed by flow cytometry. Inflammatory gene expression and protein-level STING pathway activation was evaluated in MC38 tumor lysates. diABZI-SS-DMA antitumor efficacy as a monotherapy was evaluated in MC38 colorectal cancer, orthotopic EO771 breast cancer, or orthotopic B16-F10 melanoma models in immunocompetent C57Bl/6 mice. Immunophenotyping of natural killer and T cell populations in the EO771 TME was performed by flow cytometry. Combination efficacy with α-PD-1 was evaluated in the EO771 model. Safety was assessed via complete blood counts, serum chemistry panels, and independent histopathological evaluation of major organs/tissues.Results diABZI-SH retained nanomolar STING agonist potency comparable to the clinically translated diABZI compound. diABZI-SS-DMA preferentially delivers diABZI to the tumor, exhibits high tumor-associated macrophage uptake, significantly increases STING-driven gene expression within the TME, and is well tolerated. Furthermore, diABZI-SS-DMA enhances antitumor immune responses in multiple murine tumor models, outperforming a leading STING agonist, diABZI, and synergizes with α-PD-1 therapy to improve outcomes in a challenging orthotopic, α-PD-1-unresponsive model.Conclusions We describe the design, synthesis, and pre-clinical evaluation of a next-generation polymeric STING agonist carrier, diABZI-SS-DMA, to improve the pharmacological profile and antitumor efficacy of diABZI. Collectively, this work establishes diABZI-functionalized RAFT polymerization chain transfer agents as a promising and enabling platform for engineering of next-generation polymeric carriers for the systemic delivery of STING agonists to eradicate solid tumors and potentiate ICB therapy responses in immunologically cold, α-PD-1-unresponsive tumors.
Institution: Vanderbilt University
Language: English
Subfield: Biomaterials
Field: Materials Science
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225152506