STING-Activating Polymer-Drug Conjugates for Cancer Immunotherapy
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Date
2025-02-06
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Abstract
Cancer remains the second leading cause of death in the United States. Immunotherapies, such as immune checkpoint blockade, are shifting the paradigm of cancer treatment by invigorating the immune system’s natural mechanism of recognizing and eliminating the disease. However, current treatments only benefit a minority of cancer patients. Low response rates are typically correlated to immunologically “cold” tumors, meaning they lack sufficient proinflammatory cell types such as activated macrophages, activated dendritic cells, and CD8+ cytotoxic T-cells. Therefore, there is a need for therapeutic systems that will shift tumors towards an immunogenically “hot” phenotype. One promising strategy is to activate the stimulator of interferon genes (STING) pathway, which triggers a type I interferon (IFN-I)-driven inflammatory response that enhances T cell priming, activation, and tumor infiltration. Although STING agonists are currently explored in clinical trials, most are limited to intratumoral routes of administration, which are not ideal for all patients and tumor types. Small molecule STING agonists, such as GlaxoSmithKline’s diABZI, have been developed for systemic administration; however, these clear rapidly and activate STING indiscriminately, lacking tumor-specific infiltration which can lead to unwanted systemic inflammation and non-optimal efficacy.
To address these drug delivery challenges, we have designed a STING-Activating Polymer-drug Conjugate (SAPCon) to enhance pharmacokinetics, biodistribution, and tumor accumulation of a modified STING agonist to enrich activation within the tumor and promote antitumor immunity. By modifying a diABZI molecule for chemical-conjugation to a clickable polymer platform and intracellular drug release through cathepsin cleavage, we demonstrate that drug circulation time and tumor accumulation increase with polymer molecular weight. We also report the unique finding that even non-cleavable diABZI-polymer constructs can activate STING. SAPCon promotes an immunogenic tumor microenvironment, resulting tumor growth inhibition, prolonged survival, and immunological memory in orthotopic breast cancer models. We also employed a liver-targeted, STING siRNA-loaded lipid nanoparticle to knockdown STING activation within the liver to further mitigate off-target activation and reduce serum cytokine release, typically attributed to concerning side effects in the clinic. These results position SAPCon as a modular and programmable platform for improving the efficacy and safety of systemically administered STING agonists for cancer immunotherapy.
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Immunotherapy, oncology, polymers, smart-materials