The tRNA methyltransferase DNMT2 (TRDMT1) plays a crucial role in various biological functions; however, its role in cancer, particularly in liver cancer, remains incompletely understood. In this study, we demonstrate that high DNMT2 expression is negatively correlated with prognosis in clinical liver cancer patients. A series of in vitro and in vivo experiments showed that DNMT2 promotes the proliferation, colony formation, and metastasis of hepatocellular carcinoma cells. We identified the pro-apoptotic gene TNFSF10 (TRAIL) as a downstream target of DNMT2, regulated by the N6-methyladenosine (m6A) demethylase FTO. Epigenetically, DNMT2 deletion increased FTO expression, leading to a reduction in m6A methylation levels. FTO upregulated TNFSF10 expression, significantly reducing the proliferation and metastasis of DNMT2-deficient hepatocellular carcinoma cells. Furthermore, DNMT2 deletion was shown to significantly upregulate chemokine expression in tumors. Finally, we demonstrated that the NF-κB inhibitor Bortezomib further enhances DNMT2 deletion-induced apoptosis in hepatocellular carcinoma cells. This study reveals DNMT2's role in liver cancer and presents a new therapeutic target for future treatments.

DNA methyltransferase inhibitors (DNMTis) have found widespread application in the management of cancer. Zebularine (Zeb), functioning as a demethylating agent, has exhibited notable advantages and enhanced therapeutic efficacy in the realm of tumour immunotherapy. Nevertheless, due to its lack of targeted functionality, standalone Zeb therapy necessitates the administration of a substantially higher dosage. In this investigation, we have devised an innovative nanodrug formulation, comprising the DNA methyltransferase inhibitor Zeb and pH-responsive chitosan (CS), hereinafter referred to as CS-Zeb nanoparticles (NPs). Our findings have unveiled that CS-Zeb NPs manifest heightened drug release within an acidic milieu (pH 5.5) in comparison to a neutral environment (pH 7.4). Furthermore, in vivo studies have conclusively affirmed that, in contrast to equivalent quantities of Zeb in isolation, the nanocomplex significantly curtailed tumour burden and protracted the survival duration of the B16F10 tumour-bearing murine model. Additionally, CS-Zeb NPs elicited an augmentation of CD8+ T cells within the peripheral circulation of mice and tumour-infiltrating lymphocytes (TILs). Notably, the dosage of CS-Zeb NPs was reduced by a remarkable 70-fold when juxtaposed with Zeb administered in isolation. To summarise, our study underscores the potential of CS-Zeb NPs as an alternative chemotherapeutic agent for cancer treatment.

Cyclic GMP-AMP (cGAMP) serves as a pivotal second messenger in the cGAS‒STING innate immune signaling pathway and plays a critical role in antiviral and antitumor immunity; however, its regulatory mechanisms governing the epitranscriptome remain to be elucidated. In this study, m⁶A methylation sequencing revealed that cGAMP induces dynamic changes in m⁶A modification in L929 and B16F10 cells. Mechanistic investigations revealed that cGAMP treatment significantly downregulated the expression of the RNA demethylase FTO. Although FTO deficiency suppresses cGAMP-induced interferon-stimulated gene (ISG) expression and IFN-β secretion, FTO may act as a critical node bridging cGAMP signaling and the interferon response. Further analysis revealed that the dynamic m⁶A regulation of ISGs, such as DDX58, is closely associated with the prognosis of tumor patients and immune cell infiltration. In vivo experiments confirmed that the targeted inhibition of FTO in combination with cGAMP exerts a synergistic antitumor effect, significantly suppressing tumor growth and prolonging survival. Overall, this study reveals the core mechanism of the "cGAMP-FTO-m⁶A" axis in innate immunity and tumor progression. These findings provide a theoretical foundation for the development of novel immunotherapies targeting the epitranscriptome.

Myeloid lineages exhibit prominent enrichment and profound heterogeneity within the pancreatic ductal adenocarcinoma (PDAC) microenvironment, significantly impacting clinical outcomes. Here, we analyzed 45,705 high-quality myeloid cells from patient-matched tumor and blood samples, with normal blood and tissues as controls. This revealed two tumor-promoting subsets: GBP5⁺ neutrophils sustaining a persistent pro-inflammatory circuit, presumably mediated by STAT3, and THBS1⁺ monocytes putatively orchestrating immunosuppression via Amphiregulin-driven differentiation blockade. We developed moGT, a heterogeneous graph transformer integrating multi-omic profiles with myeloid cellular abundance. moGT deconvolutes PDAC into four molecular subtypes governed by specific myeloid ecosystems (ECs), architectures supported by spatial transcriptomics. Notably, Subtype 2 exhibits an unexpectedly poor prognosis despite a favorable ‘classical’ phenotype, characterized by a GBP5⁺ neutrophil-enriched EC and NAMPT inhibition vulnerability. Conversely, aggressive Subtype 4 is defined by a THBS1⁺ monocyte-dominated EC, showing predictive sensitivity to microtubule-targeting agents. Our cross-compartment analysis links myeloid architecture to clinical heterogeneity, providing a precision oncology framework.