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Synergistic Mn-MOF Activation of Pistol Ribozymes for Cancer Immunotherapy

ABSTRACT: Checkpoint blockade therapies targeting PD-L1 have revolutionized cancer immunotherapy, yet their efficacy is constrained by systemic immune toxicity and inadequate immune infiltration in certain tumor types. Here, we introduce a synergistic gene-silencing nanosystem based on a target-selective Pistol ribozyme (PS473) encapsulated within a manganese-based, pH-responsive metal-organic framework (NKMOF-101-[Mn]). The engineered PS473 exhibited high cleavage efficiency toward GU-rich PD-L1 mRNA motifs and was further activated by Mn2 + cofactors. NKMOF-101-[Mn] not only protects the ribozyme from nuclease degradation but also enables localized Mn2 + release to increase catalytic activity and innate immune signaling under the acidic tumor microenvironment. In vitro, PS473@NKMOF-101-[Mn] markedly suppressed PD-L1 expression and promoted macrophage activation. In the B16F10 melanoma model, this system achieved over 90% tumor inhibition, enhanced immune cell infiltration and activation, and exhibited minimal systemic toxicity. Transcriptomic profiling further revealed the upregulation of immune-related pathways, supporting a synergistic mechanism of gene silencing and immune activation. Overall, this study established a ribozyme-directed immunotherapeutic platform with strong potential for precision cancer therapy via checkpoint modulation and immune reprogramming.

ORGANISM(S): Mus musculus

PROVIDER: GSE302201 | GEO | 2026/01/01

REPOSITORIES: GEO

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Project description:Background: Previous studies have shown that EZH2 regulates tumor PD-L1 expression at the transcriptional level and has an impact on tumor immune environment and prognosis. However, whether EZH2 can regulate PD-L1 expression at the post-translational level remains unclear. Therefore, this study aims to investigate the effects of EZH2 inhibition on PD-L1 expression and protein stability in colorectal cancer cells, uncover its underlying mechanisms, and provide new therapeutic strategies for anti-tumor immune therapy. Methods: Multiple colorectal cancer cell models were used to examine the effects of EZH2 inhibition on PD-L1 expression and protein stability at both the protein and transcriptional levels. Transcriptome analysis was performed to identify differentially expressed genes associated with EZH2 inhibition and potential effectors involved in EZH2-mediated regulation of PD-L1 protein stability. Validation of candidate genes was conducted through public database analysis and knockdown or overexpression models. Finally, the combined effects of EZH2 inhibitors and anti-PD-1 immune therapy were evaluated using a mouse xenograft model. Results: We observed that inhibition of EZH2 function upregulated PD-L1 expression and enhanced its protein stability in colorectal cancer cells. Transcriptome analysis revealed that ubiquitin-specific protease 22 (USP22) played a crucial role in mediating EZH2-regulated PD-L1 protein stability. EZH2 affected USP22 expression through its classical epigenetic regulatory function, thereby modulating PD-L1 expression stability and influencing the tumor immune microenvironment. Combination treatment with EZH2 inhibitors and anti-PD-1 immune therapy improved the tumor microenvironment, promoted immune cell infiltration, and exerted synergistic anti-cancer effects. Conclusion: This study elucidated the mechanisms by EZH2 regulate PD-L1 expression and stability, providing new insights into therapeutic strategies for colorectal cancer. The combination of EZH2 inhibitors and anti-PD-1 immune therapy can synergistically enhance anti-tumor effects. These findings offer a potential therapeutic approach to improve the effectiveness of EZH2 inhibitors in cancer treatment and contribute to a better understanding of the role of EZH2 in tumor immune regulation.

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Synergistic Mn-MOF Activation of Pistol Ribozymes for Cancer Immunotherapy

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