Significance
The insufficient BBB penetration and immunosuppressive tumor microenvironment greatly diminish the efficacy of immunotherapy for glioblastoma (GBM). In this study, we prepared iRGD-modified polymeric nanoparticles, loaded with a CXCR4 antagonist (AMD3100) and a small-molecule checkpoint inhibitor of PD-L1 (BMS-1) to overcome physical barriers and reprogram the immunosuppressive microenvironment in orthotopic GBM models. In this nanoplatform, AMD3100 converted the "cold" immune microenvironment into a "hot" one, while BMS-1 synergistically counteracted PD-L1 inhibition, enhancing GBM immunotherapy. Our findings underscore the potential of dual-blockade of CXCL12/CXCR4 and PD-1/PD-L1 pathways as a complementary approach to maximize therapeutic efficacy for GBM. Moreover, our study revealed that MRI radiomics provided a clinically translatable means to assess immunotherapeutic efficacy.
Statement of significance
The insufficient BBB penetration and immunosuppressive tumor microenvironment greatly diminish the efficacy of immunotherapy for glioblastoma (GBM). In this study, we prepared iRGD-modified polymeric nanoparticles, loaded with a CXCR4 antagonist (AMD3100) and a small-molecule checkpoint inhibitor of PD-L1 (BMS-1) to overcome physical barriers and reprogram the immunosuppressive microenvironment in orthotopic GBM models. In this nanoplatform, AMD3100 converted the "cold" immune microenvironment into a "hot" one, while BMS-1 synergistically counteracted PD-L1 inhibition, enhancing GBM immunotherapy. Our findings underscore the potential of dual-blockade of CXCL12/CXCR4 and PD-1/PD-L1 pathways as a complementary approach to maximize therapeutic efficacy for GBM. Moreover, our study revealed that MRI radiomics provided a clinically translatable means to assess immunotherapeutic efficacy.