The methylation of N⁶ adenosine (m⁶A) plays a critical role in diverse biological processes. However, knowledge regarding the reconstitution of m⁶A across cancer types is still lacking. Here, we systematically analyzed the molecular alterations and clinical relevance of m⁶A regulators across > 10,000 subjects representing 33 cancer types. We found that there are widespread genetic alterations to m⁶A regulators, and that their expression levels are significantly correlated with the activity of cancer hallmark-related pathways. Moreover, m⁶A regulators were found to be potentially useful for prognostic stratification, and we identified IGF2BP3 as a potential oncogene across multiple cancer types. Our results provide a valuable resource that will guide both mechanistic and therapeutic analyses of the role of m⁶A regulators in cancer.

Metabolic dysfunction–associated steatotic liver disease (MASLD) is a chronic liver disease prevalent worldwide, with an increasing incidence associated with obesity, diabetes, and metabolic syndrome. The progression of MASLD to metabolic dysfunction–associated steatohepatitis (MASH) poses a pressing health concern, highlighting the significance of accurately identifying MASLD and its progression to MASH as a primary challenge in the field. In this study, a systematic integration of 66 immune cell types was conducted. Comprehensive analyses were performed on bulk, single-cell RNA-Seq, and clinical data to investigate the immune cell types implicated in MASLD progression thoroughly. Multiple approaches, including immune infiltration, gene expression trend analysis, weighted gene coexpression network analysis, and 4 machine learning algorithms, were used to examine the dynamic changes in genes and immune cells during MASLD progression. C-X-C motif chemokine receptor 4 and dedicator of cytokinesis 8 have been identified as potential diagnostic biomarkers for MASLD progression. Furthermore, cell communication analysis at the single-cell level revealed that the involvement of C-X-C motif chemokine receptor 4 and dedicator of cytokinesis 8 in MASLD progression is mediated through their influence on T cells. Overall, our study identified vital immune cells and a 2-gene diagnostic signature for the progression of MASLD, providing a new perspective on the diagnosis and immune-related molecular mechanisms of MASLD. These findings have important implications for developing innovative diagnostic tools and therapies for MASLD. Export

Immunotherapy has become an effective therapy for cancer treatment. However, the development of biomarkers to predict immunotherapy response still remains a challenge. We have developed the DNA Methylation Immune Score, named “MeImmS,” which can predict clinical benefits of non-small cell lung cancer (NSCLC) patients based on DNA methylation of 8 CpG sites. The 8 CpG sites regulate the expression of immune-related genes and MeImmS was related to immune-associated pathways, exhausted T cell markers and immune cells. Copy-number loss in 1p36.33 may affect the response of cancer patients to immunotherapy. In addition, SAA1, CXCL10, CCR5, CCL19, CXCL11, CXCL13, and CCL5 were found to be key immune regulatory genes in immunotherapy. Together, MeImmS discovered the heterogeneous of NSCLC patients and guided the immunotherapy of cancer patients in the future.

Cancer development involves a complex interplay between genetic and epigenetic factors, with emerging evidence highlighting the pivotal role of competitive endogenous RNA (ceRNA) networks in regulating gene expression. However, the influence of ceRNA networks by aberrant DNA methylation remains incompletely understood. In our study, we proposed DMceNet, a computational method to characterize the effects of DNA methylation on ceRNA regulatory mechanisms and apply it across eight prevalent cancers. By integrating methylation and transcriptomic data, we constructed methylation-driven ceRNA networks and identified a dominant role of lncRNAs within these networks in two key ways: (i) 17 cancer-shared differential methylation lncRNAs (DMlncs), including PVT1 and CASC2, form a Common Cancer Network (CCN) affecting key pathways such as the G2/M checkpoint, and (ii) 24 cancer-specific DMlncs construct unique ceRNA networks for each cancer type. For instance, in LUAD and STAD, hypomethylation drives DMlncs like PCAT6 and MINCR, disrupting the Wnt signaling pathway and apoptosis. We further investigated the characteristics of these methylation-driven ceRNA networks at the cellular level, revealing how methylation-driven dysregulation varies across distinct cell populations within the tumor microenvironment. Our findings also demonstrate the prognostic potential of cancer-specific ceRNA relationships, highlighting their relevance in predicting patient survival outcomes. This integrated transcriptomic and epigenomic analysis provides new insights into cancer biology and regulatory mechanisms.