Effect of nanobody-STING agonists on the tumor microenvironment and adoptive cell therapy for solid tumors.

e14601 Background: Adoptive cell therapies (ACT), including TCR- and CAR-engineered T cells, have demonstrated durable clinical benefit in hematologic malignancies but have shown limited efficacy in solid tumors due to poor T cell infiltration, functional suppression, and early exhaustion within the tumor microenvironment (TME). Strategies to remodel the TME and support T cell function are therefore a major clinical priority. Activation of the stimulator of interferon genes (STING) pathway can induce antitumor inflammation and innate immune activation; however, clinical translation of STING agonists has been limited by poor tumor accumulation and dose-limiting systemic toxicity, often requiring intratumoral administration. We hypothesized that systemic, yet tumor-enriched STING activation could safely reprogram the TME and enhance the therapeutic efficacy of ACT in solid tumors. Methods: We developed an albumin-hitchhiking nanobody–STING agonist (AHNSA) platform designed to exert significantly more effects in the TME. AHNSA was evaluated as an adjuvant to ACT in a TCR-transgenic OT-I T cell transfer model using MC38-OVA tumors. Antitumor efficacy and survival were assessed by tumor volume measurements and Kaplan-Meier survival analyses. Tumor-infiltrating immune populations and transferred T cells were analyzed by flow cytometry and immunohistochemistry to evaluate innate immune activation, T cell infiltration, proliferation, functional state, and expression of exhaustion-associated markers, as well as global changes in TME composition. Results: Systemic administration of AHNSA following ACT resulted in significantly improved tumor control and survival compared with ACT alone. AHNSA treatment increased intratumoral accumulation of dendritic cells and inflammatory macrophages, consistent with STING-mediated innate immune activation, and significantly enhanced infiltration of adoptively transferred T cells. Transferred T cells exhibited increased activation and proliferation with reduced expression of exhaustion markers (PD1, LAG3), indicating improved functional persistence. Immune profiling revealed a coordinated shift toward a pro-inflammatory TME, including enrichment of CD8⁺ T cells and antigen-presenting cells and depletion of immunosuppressive populations such as myeloid-derived suppressor cells, M2 macrophages, and regulatory T cells. Conclusions: Targeted systemic STING agonism using an albumin-hitchhiking nanobody platform overcomes key delivery and toxicity barriers associated with STING activation and potently enhances adoptive T cell therapy by reprogramming the solid tumor microenvironment. These findings support a clinically relevant combination strategy to improve the efficacy of cellular immunotherapies in solid tumors and provide a strong rationale for translational development.