Tumor Microenvironment Sequential Drug/Gene Delivery Nanosystem for Realizing Multistage Boosting of Cancer–Immunity Cycle on Cancer Immunotherapy

The antitumor immune response of cancer immunotherapy is a cascade of cancer–immunity cycles (CIC). The immunosuppression of the tumor microenvironment and low immunogenicity of tumor cells, insufficient T lymphocyte activation, trafficking, and infiltration caused the failure to initiate and run the continuous multistage CIC, leading to unsatisfactory cancer immunotherapy outcomes. A doxorubicin/interleukin-12 plasmid DNA/celecoxib (DOX/pIL-12/CXB) combination strategy was designed by targeting the cascade CIC. Then, an intratumoral CXB-detachable nanosystem, or DOX/PAC/pIL-12 micelleplexes, was developed for sequential drug/gene delivery to facilitate the multistage boosting of CIC on synergistic cancer immunotherapy. The DOX/PAC/pIL-12 micelleplexes could program intratumorally sequential release of CXB to remodulate the tumor microenvironment immunosuppression by suppressing the cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) pathway. The smaller sizes and surface charge-switched micelleplexes facilitated the codelivery and corelease of DOX and pIL-12 inside 4T1 tumor cells. These micelleplexes exerted a synergistic antitumor immune response using CIC cascade activation and amplification, providing therapeutic antitumor and antimetastasis efficacy. The drug/gene sequential delivery nanosystem provides a complete CIC-boosted combinatory strategy for developing immunotherapy against cancer.