Reprogramming Tumor-Associated Macrophage by Ornithine Decarboxylase Inhibitor and Immune Checkpoint for Orthotopic...

Immune-suppressive tumor-associated macrophages (TAMs) that infiltrate the tumor microenvironment (TME), along with the presence of the blood-brain barrier (BBB), influence the effectiveness of immunotherapy for glioblastoma. In this study, we report the use of difluoromethylornithine (DFMO), aPD-L1, and Indocyanine Green (ICG) in combination with target TAMs for their repolarization. DFMO repolarizes TAMs by inhibiting the expression of aconitate decarboxylase 1 (ACOD1), while aPD-L1 blocks the PD-1/PD-L1 immune checkpoint on TAMs, achieving efficient phenotypic switching and enhancing the phagocytic activity against glioblastoma (GBM). When combined with the photothermal agent ICG, the photothermal effect induces immunogenic tumor cell death and further strengthens the repolarization of TAMs. This increases the conversion efficiency of TAMs, reverses immune suppression at the tumor site, and transforms the anti-inflammatory "cold" tumor into a pro-inflammatory "hot" tumor. This approach showed better therapeutic effects in an orthotopic glioma model in mice, with the repolarization of our combined treatment DFMO + N-aP@ICG (nanovesicles containing aPD-L1 and ICG), increasing by 179% compared to other combined treatments for glioma. In summary, we propose this innovative immunotherapy for glioma, which effectively penetrates the blood-brain barrier, targets M2-TAMs, enhances the aPD-L1 immune response, and inhibits the proliferation of glioma.