Immuno-Initiator Rectifies Immunodeficiency to Restore Immune Function and Potentiate Immunotherapy against IDH Mutant Glioma.

Abstract

Glioma induces distinctive immunodeficiency, impeding functional tumor-infiltrating T cells and resisting immunotherapy. Both systemic and local immunosuppression contribute to attenuating T-cell-mediated antitumor immunity, posing a challenge to developing effective counterstrategies. Herein, we introduce "Immuno-initiator" coated with glioma cell membrane and glucose derivative, for delivering immune modulator α-Mangostin (α-M) and photosensitizer indocyanine green (ICG) to restore immune function and evoke potent immune responses against isocitrate dehydrogenase mutant (IDH-mt) glioma. Our investigation reveals that immuno-initiator employs α-M to mitigate systemic immunosuppression and increase systemic T cells, and synergize with ICG to enhance reactive oxygen species production upon laser exposure, thereby inducing immunogenic glioma cell death to overcome local immunosuppression and facilitate functional T-cell infiltration. Crucially, when coupled with immune checkpoint inhibitor therapy, Immuno-initiator demonstrates synergistic efficacy, yielding long-term survival in 33.3% of mice by inhibiting IDH-mt glioma growth post laser irradiation. These findings underscore the potential of concurrently addressing systemic and local immunosuppression to rectify immunodeficiency, offering a clinically feasible therapeutic platform for combating brain malignancies.