Perdurable PD-1 blockage awakes anti-tumor immunity suppressed by precise chemotherapy

The application of nanocarriers as drug delivery system for chemotherapeutic drugs has become a research hotspot in cancer treatment. Chemotherapy with high tumor-targeting accuracy and drug release specificity is the key to improve the efficacy of tumor chemotherapy and reduce the side effects caused by repeated doses drugs. Here, we synthesized a redox-sensitive nano-micelle formed by hyaluronic acid (HA) conjugated with D-alpha-tocopherol succinate (TOS) using a disulfide bond as the linker (HA-SS-TOS, HSST), which could actively accumulate to the tumor sites and metastasis cancer cells with high expression of CD44. The micelles could dissociate under the high GSH level in cancer cells, triggering a release of paclitaxel (PTX). Surprisingly, the precise chemotherapy instead induced a suppressive tendency of immune system, manifested by a significant increase in TGF-beta, which weakened the therapeutic effect of micelles. Moreover, the high levels of TGF-beta might be related to the increased drug-resistance of cancer cells. Research has shown that PD-1 pathway blockade can result in reduction in TGF-beta expression, thus, a PLGA microsphere encapsulating PD-1 antagonist peptides A12 (A12@PLGA) was further prepared to activate the host immune response. Our data indicated that PTX-loaded HSST could accurately "find" the tumors as well as metastasis cancer cells, and efficiently kill most of them. The joining of a durable PD-1 blockage significantly boosted the efficacy of PTX@HSST on multiple tumor models, including lung metastatic tumors and even multidrug-resistant tumors. Thus, our work presented an optimal chemo-immunotherapy combined system, which shows profound significance for future cancer therapy in clinic.