Improved Hypoxic Microenvironment By Nanoformulation For Effective T Cell Therapy In Mice Model.

Abstract

Introduction: Adoptive cell therapy (ACT) has emerged as a powerful strategy for eliciting tumor regression. However, its efficacy in solid tumors remains limited, primarily due to the immunosuppressive tumor microenvironment (TME). We developed a tumor microenvironment-responsive mesoporous silica nanosphere (MSN) formulation co-loaded with the immunostimulant imiquimod (R837), zinc peroxide (ZnO₂), and manganese peroxide (MnO₂) to alleviate hypoxia and enhance dendritic cell (DC)-mediated antitumor immunity.

Methods: The immunostimulatory efficacy of our nanoparticles was evaluated in vitro using DC activation assays and in vivo in an H22 murine hepatocellular carcinoma model. Flow cytometry was employed to assess immune cell populations in tumors and lymph nodes, while immunofluorescence microscopy was used to analyze tumor hypoxia and T cell infiltration.

Results: The oxygen-generating MSN formulation effectively alleviated intratumoral hypoxia, promoted DC maturation (CD80⁺CD86⁺), and facilitated effector CD8⁺ T cell infiltration into tumors. In vivo, co-administration of the nanoformulation with ACT led to enhanced tumor suppression and systemic antitumor immune responses without evident toxicity to major organs.

Conclusion: This oxygen-producing immunomodulatory nanoplatform remodels the immunosuppressive TME and significantly enhances the efficacy of ACT in solid tumors, offering a promising strategy for overcoming current barriers in T cell-based immunotherapy.