A M2-like tumor-associated macrophage-targeted nanoparticulate TLR7/8 agonist, UI-102, reprograms its phenotypes to induce potent anti-tumor immunity

Background: Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and exhibit functionally distinct phenotypes: anti-tumoral M1 and pro-tumoral M2 TAMs. The predominance of M2-like TAMs promotes tumor growth, angiogenesis, and immunosuppression, making them a promising target for cancer immunotherapy. M2-like TAMs frequently express the C-type lectin DC-SIGN/CD209, and we discovered that nanoparticles composed of pullulan polysaccharide are preferentially engulfed by DC-SIGN-expressing M2 macrophages. Leveraging this property, we developed UI-102, a novel nanoparticulate TLR7/8 agonist using pullulan nanoparticles as an M2 TAM-targeted drug delivery system. This study aimed to evaluate the anti-tumor efficacy and mechanism of action of UI-102, focusing on its ability to reprogram TAM phenotypes and activate anti-tumor immunity. Methods: The anti-tumor activity of UI-102 was assessed in multiple murine syngeneic subcutaneous tumor models. Mechanistic studies included analysis of TAM phenotypic shifts and activation of the anti-tumor immune cascade. Biodistribution and TAM accumulation were examined in an orthotopic mouse model, comparing UI-102 with resiquimod sulfate and the naked TLR7/8 agonist used in the UI-102 formulation. Results: UI-102 exhibited broad and potent anti-tumor activity across diverse cancer models, correlating with the degree of myeloid/macrophage infiltration in the TME. Despite a short plasma half-life (T1/2), UI-102 rapidly and selectively accumulated in TAMs in the orthotopic model. This targeted delivery induced a robust phenotypic switch from immunosuppressive TAMs to an M1-like state, triggering downstream anti-tumor immune cascades. These changes were associated with increased infiltration of T cells and NK cells and the induction of tumor antigen-specific CD8+ T cells. The anti-tumor effects of UI-102 were significantly superior to those of control agents, including resiquimod sulfate and the naked TLR7/8 agonist. Conclusion: UI-102 effectively targets and reprograms immunosuppressive TAMs to an M1-like phenotype, thereby unleashing a strong anti-tumor immune response. This unique mechanism positions UI-102 as a promising novel immunotherapeutic agent for a wide range of solid tumors. A first-in-human clinical trial of UI-102 in solid tumors is planned for initiation in Q1 2026.