Nanobody:STING agonists reprogram the tumor microenvironment and improve adoptive cell therapy for solid tumors

Adoptive cell therapy (ACT) has shown curative potential in hematologic malignancies but remains largely ineffective in solid tumors due to an immunosuppressive tumor microenvironment (TME) that limits T cell infiltration, activation, and persistence. Pharmacologic activation of the stimulator of interferon genes (STING) pathway can induce tumor inflammation and innate immune activation; however, clinical translation of STING agonists has been constrained by poor tumor accumulation and dose-limiting systemic toxicity, often necessitating intratumoral delivery. We hypothesized that systemic yet tumor-enriched STING activation, achieved through an albumin-hitchhiking nanobody-STING agonist platform (AHNSA), could safely reprogram the TME and function as a programmable adjuvant to ACT in solid tumors. AHNSA conjugates were systemically administered in combination with ACT in a TCR-transgenic OT-I T cell transfer model bearing MC38-OVA tumors. AHNSA was administered in a triple dose 4 days apart, 3 days after ACT. Tumor growth and survival were assessed by caliper measurements every alternate day and Kaplan-Meier survival analysis. 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 exhaustion, as well as global remodeling of the TME. Systemic AHNSA administration following ACT significantly improved survival compared with ACT alone. AHNSA treatment increased tumor infiltration of innate immune cells and adoptively transferred T cells. Transferred T cells exhibited enhanced activation and proliferation with reduced expression of exhaustion markers (PD-1, LAG3, TIM3), consistent with improved effector quality. Comprehensive immune profiling revealed a STING-driven shift toward a pro-inflammatory TME, characterized by enrichment of dendritic cells, M1 macrophages, and CD8⁺ T cells, alongside depletion of immunosuppressive populations including myeloid-derived suppressor cells, M2 macrophages, and regulatory T cells. These findings indicate coordinated innate-to-adaptive immune reprogramming rather than isolated cellular effects. Ongoing studies demonstrate extension of this approach to an immunocompetent CAR-T cell model. Targeted systemic STING agonism via albumin-hitchhiking nanobody conjugates overcomes key delivery and toxicity barriers of STING therapy and potently enhances ACT efficacy by reprogramming the solid tumor microenvironment. This strategy represents a broadly applicable immunomodulatory platform to unlock the full potential of cellular immunotherapies in solid tumors.