STING-Activating\nPolymer–Drug Conjugates for\nCancer Immunotherapy

The stimulator of\ninterferon genes (STING) pathway links innate\nand adaptive antitumor immunity and therefore plays an important role\nin cancer immune surveillance. This has prompted widespread development\nof STING agonists for cancer immunotherapy, but pharmacological barriers\ncontinue to limit the clinical impact of STING agonists and motivate\nthe development of drug delivery systems to improve their efficacy\nand/or safety. We developed SAPCon, a STING-activating polymer–drug\nconjugate platform based on strain-promoted azide–alkyne cycloaddition\nof a novel dimeric amidobenzimidazole (diABZI) STING prodrug to hydrophilic\npoly(dimethylacrylamide-<i>co</i>-azido-ethylmethacrylate)\npolymer chains through a cathepsin B-responsive linker to increase\ncirculation time and enable passive tumor accumulation. We found that\nintravenously administered SAPCon accumulated at tumor sites, where\nit was endocytosed by tumor-associated myeloid cells, resulting in\nincreased STING activation in the tumor tissue. Consequently, SAPCon\npromoted an immunogenic tumor microenvironment characterized by increased\nfrequency of activated macrophages and dendritic cells and improved\ninfiltration of CD8<sup>+</sup> T cells, resulting in inhibition of\ntumor growth, prolonged survival, and enhanced response to anti-PD-1\nimmune checkpoint blockade in orthotopic breast cancer models. Collectively,\nthese studies position SAPCon as a modular and programmable platform\nfor improving the efficacy of systemically administered STING agonists\nfor cancer immunotherapy.