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A CTL-inspired Killing System Reveals Ultralow-dose Chemotherapy is Sufficient for Inducing a Pyroptosis-mediated Antitumour Immune Function

ABSTRACT: 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 proinflammatory type of 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 43 µg kg-1 DOX was sufficient for GSDME-positive tumour regression with negligible injuries to major organs. Notably, 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, but high-dose DOX led to poor T cells infiltration which caused immunosuppression and lung metastasis. 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

INSTRUMENT(S): 6410 Triple Quadrupole LC/MS

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture, Macrophage

SUBMITTER: hao yin

LAB HEAD: hao yin

PROVIDER: PXD047873 | Pride | 2024-02-23

REPOSITORIES: Pride

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Project description:Lytic cell death, such as pyroptosis, can trigger antitumour immune response. However, cancerous cells avoid lytic cell death by various escape mechanisms acquired through evolution. Moreover, persistent uncontrolled lytic cell death may inversely cause hyperactive immune response or T-cell exhaustion. Therefore, an oncolytic system capable of breaking through natural restrictions to dissolve cancer cells in a catalytic and controllable manner is needed. Here, we established a microscale cytotoxic T-cell-inspired oncolytic system (TIOs) by which the NIR light-generated reactive oxygen species could precisely rupture the plasma membrane of cancer cells by direct lipids peroxidation. Similar as cytotoxic T cells, TIOs present antigen-based cell recognition and catalytic cell-lysis ability; thus, the TIOs can trigger significant oncolysis and immune response in vivo. The TIOs exhibited exceptional tumour targeting and penetration without any inflammatory risk. We applied TIOs to antitumour therapies, which showed kinds of tumour models could be cleared efficiently with negligible injuries to major organs. Tumour regression was correlated with oncolysis-mediated inflammation and T-cell-based antitumor immune response. Owing to the tuneability of TIOs-mediated oncolysis, we further revealed that though the T-cell recruitment was comparable, the high-intense oncolysis induced acute inflammation in initial stage was crucial for potent antitumour immunity and immune memory effects, and low-intense oncolysis resulted in T-cell exhaustion and tumour progression. To the mice received low-intense oncolysis, although synergizing with anti-PD-1 therapies or STING activation rescued the immune dysfunction, STING activation released a more powerful boost to durative antitumour immunity by reshaping the stemness of CD8+ T cells. Our study provides new insights to design the oncolytic systems for antitumour immunity. Moreover, our application suggests that the intensity of initial inflammation plays a decisive role in maintaining oncolysis-induced antitumour immune function and STING activation holds promise for reversal of immune dysfunction due to T-cell exhaustion.

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A CTL-inspired Killing System Reveals Ultralow-dose Chemotherapy is Sufficient for Inducing a Pyroptosis-mediated Antitumour Immune Function

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