Potentiation of a Porous Silicon Therapeutic Vaccine in Colorectal Cancer via Oxaliplatin-Mediated Regulation of Myeloid-Driven Immunosuppression.

Although immunotherapy has shown great promise in treating various types of cancer, advanced tumors are often refractory due to a highly immunosuppressive tumor microenvironment (TME). We previously engineered a cancer therapeutic vaccine platform, µGCVax, by co-loading tumor antigen peptides, STING and TLR9 agonists into porous silicon microparticles. While effective in models with lower disease burden, its efficacy against advanced colorectal cancer (CRC) was less promising due to the accumulation of myeloid-derived suppressor cells (MDSCs) in TMEs. In this study, we investigated whether µGCVax-based immunotherapy in advanced CRCs could be potentiated via regulating MDSCs to reprogram the TME. In an advanced CT26 murine CRC model, we assessed µGCVax in combination with oxaliplatin, a standard CRC chemotherapeutic with established immunomodulatory effects. We demonstrated that oxaliplatin was preferentially taken up by monocytic MDSCs (M-MDSCs) and effectively reduced their abundance in the bone marrow, blood, spleen, and tumor. Relief of this immunosuppressive TME increased intratumoral infiltration of antigen-specific CD8+ T cells. Ultimately, the combination of oxaliplatin with µGCVax induced robust regression of established CRC tumors. These findings highlight that oxaliplatin synergizes with µGCVax by overcoming MDSC-mediated immunosuppression and enhancing antitumor immunity, representing a promising chemo-immunotherapy strategy for advanced CRC.