Targeted delivery of sting agonists to regulatory T cells for cancer immunotherapy

The National Institute of Allergy and Infectious Diseases awarded Vanderbilt University $152,600 on November 29, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) for research on targeted delivery of STING agonists to regulatory T cells for cancer immunotherapy.

The project, designated F32AI200412, focuses on engineering a bispecific nanobody-STING agonist conjugate designed to selectively reprogram regulatory T cells to enhance anti-tumor immunity while minimizing systemic toxicity. The work addresses the limited efficacy of immune checkpoint blockade therapies in patients with immunosuppressive tumor microenvironments by leveraging a recently identified phenomenon: activating the STING pathway in regulatory T cells induces metabolic reprogramming toward an anti-tumor phenotype. The engineered conjugate incorporates a CTLA4-binding domain for treg-specific targeting and an albumin-binding domain to enhance pharmacokinetics and circulation time. Optimization efforts will assess therapeutic efficacy through functional and metabolic assays evaluating changes in regulatory T cell metabolism, immunosuppressive markers, and cytokine production.

Performance occurs at Vanderbilt University in Nashville, Tennessee, with a period of performance from November 29, 2026, through November 28, 2028. This is a Project Grant assistance type.

Abstract

And abstract immune checkpoint blockade (ICB) therapies have transformed cancer treatment but demonstrate limited efficacy in many patients due to an immunosuppressive tumor microenvironment (TME). Regulatory T cells (TREGS) are key mediators of this suppression, dampening cytotoxic T lymphocyte (CTL) activity and enabling immune evasion. Current treg-targeting therapies, such as CTLA4 inhibitors, show promise but are limited by systemic toxicity, highlighting the urgent need for innovative approaches to modulate treg activity without compromising peripheral immune function. This proposal pioneers a novel drug delivery and immunomodulation strategy to overcome these challenges by engineering a bispecific nanobody-sting agonist conjugate (BINSC) to reprogram TREGS. We leverage a recently identified phenomenon: activating the sting pathway in TREGS induces metabolic reprogramming and a shift toward an anti-tumor, effector T cell-like phenotype. However, systemic delivery of sting agonists is hindered by poor pharmacological properties and low specificity. To address these issues, we propose engineering a bispecific nanobody-sting agonist conjugate (BINSC) designed to selectively target TREGS through a CTLA4-binding domain, which is predominantly expressed on TREGS, coupled with an albumin-binding domain to enhance pharmacokinetics and prolong circulation time. This platform aims to transiently reprogram TREGS to a more inflammatory phenotype and enhance anti-tumor immunity. Aim 1 will optimize bispecific nanobody-sting conjugate (BINSC) design for treg-specific drug delivery by tuning targeting domains, domain orientation, interdomain linkers, and drug linkers to enhance treg binding, internalization, and sting agonist release. Functional and metabolic assays will assess therapeutic efficacy by evaluating changes in treg metabolism, immunosuppressive markers, and cytokine production. In vivo studies will characterize pharmacokinetics, biodistribution, and treg-specific sting activation in a B16.F10 melanoma model. Aim 2 will evaluate the therapeutic potential and immunological consequences of sting activation in TREGS within the tumor microenvironment (TME) and peripheral tissues. Using complementary approaches-adoptive T cell transfer of EX vivo sting-treated TREGS and pharmacologic delivery via a first- generation BINSC-we will assess treg phenotypic shifts, treatment efficacy, and safety in preclinical models. Comprehensive analysis will focus on immunophenotypic changes in the TME and off-target organs and determine whether sting-reprogrammed TREGS can elicit an effective anti-tumor immune response. This work aims to define principles of treg-targeted drug delivery and elucidate how transient treg reprogramming via sting activation enhances anti-tumor immunity without depletion. This innovative approach promises to optimize immunotherapy by creating a hot TME that promotes tumor rejection. These studies will provide critical insights into targeted drug delivery and immunoengineering, offering a promising strategy to boost cancer immunotherapy outcomes.