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Microenvironment-Responsive Prodrug-Induced Pyroptosis Boosts Cancer Immunotherapy.

ABSTRACT: The absence of tumor antigens leads to a low response rate, which represents a major challenge in immune checkpoint blockade (ICB) therapy. Pyroptosis, which releases tumor antigens and damage-associated molecular patterns (DAMPs) that induce antitumor immunity and boost ICB efficiency, potentially leads to injury when occurring in normal tissues. Therefore, a strategy and highly efficient agent to induce tumor-specific pyroptosis but reduce pyroptosis in normal tissues is urgently required. Here, a smart tumor microenvironmental reactive oxygen species (ROS)/glutathione (GSH) dual-responsive nano-prodrug (denoted as MCPP) with high paclitaxel (PTX) and photosensitizer purpurin 18 (P18) loading is rationally designed. The ROS/GSH dual-responsive system facilitates the nano-prodrug response to high ROS/GSH in the tumor microenvironment and achieves optimal drug release in tumors. ROS generated by P18 after laser irradiation achieves controlled release and induces tumor cell pyroptosis with PTX by chemo-photodynamic therapy. Pyroptotic tumor cells release DAMPs, thus initiating adaptive immunity, boosting ICB efficiency, achieving tumor regression, generating immunological memory, and preventing tumor recurrence. Mechanistically, chemo-photodynamic therapy and control-release PTX synergistically induce gasdermin E (GSDME)-related pyroptosis. It is speculated that inspired chemo-photodynamic therapy using the presented nano-prodrug strategy can be a smart strategy to trigger pyroptosis and augment ICB efficiency.

SUBMITTER: Xiao Y

PROVIDER: S-EPMC8693073 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Bladder cancer is known to be the most common malignant tumor in the urinary system and has a poor prognosis; thus, new targets for drug treatment are urgently needed. Pyroptosis is defined as programmed cell death in the inflammatory form mediated by the gasdermin protein. It has therapeutic potential due to the synergistic effect of radiotherapy and chemotherapy, can reverse chemotherapy resistance, is able to regulate the body environment to alter tumor metabolism, and may enhance the response rate of the immune checkpoint inhibitor. Accordingly, this study attempted to explore the role of pyroptosis in bladder cancer. A prognostic model based on five pyroptosis-related genes was constructed by conducting univariate Cox survival and LASSO regression analyses using The Cancer Genome Atlas (TCGA) cohort. Patients were divided into high- and low-risk groups according to the median risk score, with all five PRGs having downregulated expression in the high-risk group. The high-risk group was shown to have a worse prognosis than the low-risk group, and survival differences between the two groups were then validated in the Gene Expression Omnibus (GEO) cohort. Moreover, the ROC curves demonstrated the model's moderate predictive ability. The univariate and multivariate Cox regression analyses indicated that risk scores were found to serve as an independent prognosis factor for OS in bladder cancer patients. In addition, the high-risk group was observed to be associated with advanced N and TNM stages. A nomogram combining risk scores and clinical features was then established, with the ROC curve indicating that the AUC of TCGA training cohort in 3 and 5 years was 0.789 and 0.775, respectively. The calibration curve exhibited a high consistency between the actual survival rate and the predicted rate. Furthermore, the GO and KEGG analyses found that antigen processing and presentation of exogenous antigen, exogenous peptide antigen, and peptide antigen were enriched in the low-risk group. A higher abundance of tumor-infiltrating immune cells and additional active immune pathways were also noted in the low-risk group. In addition, immunotherapy biomarkers, including TMB, PD1, PD-L1, CTLA4, and LAG3, were shown to have higher levels in the low-risk group. Therefore, patients in the low-risk group may be potential responders to immune checkpoint inhibitors.

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Microenvironment-Responsive Prodrug-Induced Pyroptosis Boosts Cancer Immunotherapy.

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