Nanobody-STING Agonist Reprogram the Tumor Microenvironment and Improve Adoptive Cell Therapy for Solid Tumors 2309144

Introduction Adoptive cell therapy (ACT) has demonstrated efficacy in hematologic malignancies but remains limited in solid tumors due to an immunosuppressive tumor microenvironment (TME) that restricts T cell infiltration, activation, and persistence. Activation of the stimulator of interferon genes (STING) pathway can reprogram the TME toward inflammation; however, systemic STING agonist delivery is hindered by poor tumor accumulation and dose-limiting toxicity. We hypothesized that targeted systemic delivery of a STING agonist using an albumin-hitchhiking nanobody platform could safely enhance ACT efficacy in solid tumors by reversing the immunosuppressive TME. Methods We developed albumin-hitchhiking nanobody—STING agonists (AHNSA) and evaluated them as an adjuvant to ACT in a TCR-transgenic OTI T cell transfer model using MC38-OVA tumors. Dosing and timing of AHNSA relative to ACT were optimized. Tumor-infiltrating immune cells and transferred T cells were analyzed by flow cytometry and IHC to assess activation, proliferation, exhaustion, and cytotoxic potential, as well as global changes in TME composition. Results Systemic AHNSA administration following OTI T cell transfer significantly improved survival compared to ACT alone. AHNSA treatment increased infiltration of both innate immune cells and adoptively transferred T cells into tumors. Transferred T cells displayed enhanced activation and proliferation with reduced expression of exhaustion markers. Bulk tumor immune profiling revealed enrichment of pro-inflammatory populations, including M1 macrophages, dendritic cells, and CD8+ T cells, alongside depletion of immunosuppressive subsets such as myeloid-derived suppressor cells, M2 macrophages, and regulatory T cells. These findings indicate effective reversal of TME immunosuppression. Ongoing studies are extending this approach to a fully immunocompetent CAR-T model. Conclusion AHNSA represents a promising strategy to overcome TME-mediated resistance and enhance ACT efficacy in solid tumors.