CTL-inspired Killing System Using Ultralow-dose Chemical-drugs to Induce A Pyroptosis-mediated Antitumour Immune Function.

A Cytotoxic T lymphocyte-inspired system capable of using ultralow-dose chemical drugs to manipulate cell death is needed to investigate the antitumour immunotherapy. Recent studies revealed pyroptosis, a type of immunogenic cell death, could promote antitumour immune function. However, high-dose chemotherapy led to cytokine release syndrome by pyroptosis. Therefore, pyroptosis-inducing ultralow-dose chemotherapy was potential in preclinical and clinical research, but its efficacy, safety and the antitumour immune responses were not clear. Here, we established a near-infrared light controllable killing system (BIK system) by which ultralow-dose doxorubicin could be spatiotemporally transported to immunosuppressive tumour cells and mediate efficient pyroptosis. Compared with using DOX directly, the BIK system reduced total drug consumption to less than one-thirtieth the common dose in vitro. MPI imaging and fluorescence imaging showed our BIK system exhibited good tumour targeting and tumour penetration. We applied this system for pyroptosis-induced antitumor therapies, and the results showed that less than c.a. 25 μg kg -1 DOX was sufficient for GSDME-positive tumour regression with negligible injuries to major organs. Moreover, the gasdermin-deficient 4T1 tumours could be controlled by combining BIK system with decitabine treatment. The antitumour immune function were proven to correlate with the impressive efficacy of pyroptosis-inducing ultralow-dose chemotherapy, and the concomitant immune memory prevented metastasis. Compare to pyroptosis-inducing ultralow-dose chemotherapy, the boost in T-cell infiltration after high-dose DOX treatment was relative weak, and it failed to improve immunosuppression and block lung metastases. Owing to the robust antitumour immune function induced by BIK system, advanced-stage bulky tumours could be controlled or shrunken by synergizing with anti-PD-1 therapy. This study provided new insights into the design of nanoassisted systems for activating the antitumour immune function by microstimulation; our application of the BIK system suggested that ultralow-dose chemotherapy was sufficient for inducing a robust pyroptosis-mediated antitumour immune function. This article is protected by copyright. All rights reserved.