| 描述信息 |
A CTL-inspired system capable of disrupting immunosuppression to manipulate cell death is needed to investigate the immune response triggered by subtle perturbations, such as ultralow-dose drug-induced immunotherapy1,2. Recent studies revealed that pyroptosis, a proinflammatory type of cell death, could promote tumour immune function3-6. Moreover, high-dose chemotherapy leads to serious adverse events (SAEs) by inducing cytokine release syndrome via pyroptosis7-9. Therefore, pyroptosis-inducing ultralow-dose chemotherapy is potential in clinical research, but its efficacy and safety, especially the immune responses, are not clear. Here, we established a near-infrared controllable bioinspired killing (BIK) system in which ultralow-dose doxorubicin (DOX) can be spatiotemporally transported to immunosuppressive cancer cells and mediate pyroptosis. Compared with using DOX directly, the BIK system reduced total drug consumption to less than one-thirtieth the common dose. The BIK system exhibited long-term circulation and deep tumour penetration without any inflammatory risk. We applied this system for pyroptosis-induced antitumor therapy, and the results revealed that less than 43 µg/kg DOX was sufficient for GSDME-positive tumour regression with negligible injuries to major organs. The tumour immune responses were proven to correlate with the impressive efficacy of pyroptosis-inducing ultralow-dose chemotherapy, and concomitant immune memory prevented metastasis. Owing to the low systemic toxicity and robust immune response induced by pyroptosis-inducing ultralow-dose chemotherapy delivered by the BIK system , advanced-stage bulky tumours can be controlled or shrunk by a cascade of secondary pyroptotic immune activation that synergize with checkpoint blockade. This study provides new insights into the design of nanoassisted bioinspired systems for perturbing the immune system by microstimulation; our application of the BIK system suggests that ultralow-dose chemotherapy is sufficient for inducing a pyroptosis-mediated tumour immune response. |
