bims-tumhet 2026-07-26 papers

Nat Commun. 2026 Jul 18.

Epigenomic modifications define chromatin states to regulate cell-free DNA fragmentomics.

Fanglei Gong, Yuqi Pan, Huizhen Lin, Yunyun An, Mengqi Yang, Xiaoyi Liu, Yunxia Bai, Zhenyu Zhang, Bianbian Tang, Kun Zhang, Xin Zhao, Yu Zhao, Changzheng Du, Xuetong Shen, Kun Sun.

Plasma cell-free DNA (cfDNA) fragmentomics offer promising cancer biomarkers, but their molecular regulation remains elusive. Here, we investigate the role of epigenomic modifications in cfDNA fragmentation. We identify strong correlations between cfDNA fragmentomic features and various epigenetic marks measured in cfDNA. We further segment the genome into different chromatin states using histone modification signals, revealing consistent associations with cfDNA fragmentomics. The association is further validated by histone modifier perturbation experiments, confirming chromatin organization as a key regulator of cfDNA fragmentation. CfDNA fragmentomic features associated with Transposon Elements (TEs) outperform genome-wide metrics in cancer diagnosis, reflecting cancer type-specific patterns. Leveraging these insights, we develop TEANA (Transposon Element Analysis in cfDNA), an AI-empowered model using a small set of TE fragmentomic features for pan-cancer detection and tumor-origin prediction, achieving robust performance across independent cohorts. Hence, chromatin states drive cfDNA fragmentation, and dysregulated TEs provide highly informative biomarkers for cancer diagnosis.

DOI: https://doi.org/10.1038/s41467-026-75640-2

Mol Oncol. 2026 Jul 23.

Spatial biology in cancer epigenetics.

Eva Crespo-García, Manel Esteller.

Cancer develops inside organized tissue environments wherein cellular behavior is heavily influenced by local interactions and spatially restricted regulatory programs. While bulk and single-cell sequencing technologies have fundamentally revolutionized our understanding of tumor biology, these techniques often disrupt tissue architecture and therefore fail to capture the spatial context in which molecular processes occur. Spatial transcriptomics has provided important insights into tumor heterogeneity, microenvironmental organization, and cell-to-cell communication. However, gene expression alone offers only an indirect view of the regulatory mechanisms governing cellular states. The emergence of spatial epigenomic technologies now enables the investigation of chromatin accessibility, histone modifications, and DNA methylation while preserving tissue structure. Here, we discuss the current landscape of spatial epigenomics, including spatial ATAC-seq, spatial CUT&Tag, emerging spatial CUT&RUN approaches, spatial DNA methylation profiling, and multimodal strategies integrating epigenetic, transcriptional, and proteomic information within the same tissue context. Despite remaining technical and computational challenges, continued advances are expected to establish spatial epigenomics as a powerful tool for studying cancer pathways and their regulation within intact tissues.

Keywords: DNA methylation; cancer; chromatin; epigenetics; histone modifications; spatial biology

DOI: https://doi.org/10.1002/1878-0261.70310

Clin Cancer Res. 2026 Jul 23.

Landmark ctDNA molecular response represents an early predictor of immunotherapy outcomes in lung cancer: A clinical validity study.

PURPOSE: Circulating tumor DNA (ctDNA) analyses are informative as an early indicator of immunotherapy response in advanced non-small cell lung cancer (NSCLC); however, the clinical value of ctDNA molecular response requires further validation.
PATIENTS AND METHODS: As part of a prospective clinical protocol (NCT05995821), we conducted targeted error-correction sequencing of ctDNA (n=328) and matched WBC DNA (n=109) from 109 patients with metastatic NSCLC who received anti-PD-(L)1 either as monotherapy or in combination. Following cellular origin resolution of 2,818 variants, landmark molecular response (mR) was defined as undetectable ctDNA within 3-9 weeks of treatment initiation.
RESULTS: Pre-treatment ctDNA burden, but not blood tumor mutation burden, predicted survival. Implementing a tumor-naïve WBC DNA-informed approach increased the number of evaluable cases without compromising the overall accuracy of landmark ctDNA molecular responses. A direct comparison of single-timepoint on-therapy ctDNA assessment with ctDNA dynamics from baseline to the 3-9-week interval, along with an analysis of heterogeneity in molecular response within the 3-9-week window, showed that undetectable ctDNA at the landmark timepoint can effectively predict survival outcomes. A significant enrichment in landmark ctDNA mR was noted among patients with progression-free survival (PFS) ≥6 months on immunotherapy (p=2.5e-05) or chemo-immunotherapy (p=0.02). Patients in the landmark mR group had longer progression-free (p=1.6e-06) and overall survival (p=2.5e-05) than those with molecular progression.
CONCLUSIONS: Landmark ctDNA molecular response provides a real-time, accurate approach for monitoring immunotherapy clinical outcomes. Although not currently validated for regulatory use, these findings demonstrate the potential validity of ctDNA as an early endpoint of immunotherapy response.

DOI: https://doi.org/10.1158/1078-0432.CCR-26-0656

Nat Rev Clin Oncol. 2026 Jul 24.

Towards liquid biopsy-based analysis of antitumour immunity.

Klaus Pantel, Doryan Masmoudi, Catherine Alix-Panabières.

Analysis of tissue biopsy samples is the gold-standard approach to cancer diagnosis and patient selection for biomarker-guided therapies. Although spatial analyses of tumour tissue can provide important insights into local antitumour immune responses, repeated tumour biopsy is invasive and rarely feasible for monitoring dynamic immune responses over time. Technical advances have enabled multimodal analyses of cells and cellular products in peripheral blood samples, which can be obtained easily and repeatedly over the course of the disease. These liquid biopsy-based approaches cannot provide spatial information on the tumour immune microenvironment and tumour-derived material can be highly diluted in the circulation, yet they offer a unique opportunity to monitor systemic immune dynamics, anticipate responses to immunotherapies and detect emerging resistance to treatment. Thus, blood-based analyses might complement tumour tissue analysis. In this Review, we discuss insights on systemic antitumour immune responses that can be gained through the analysis of tumour-derived biomarkers in peripheral blood and/or circulating immune cells.

DOI: https://doi.org/10.1038/s41571-026-01181-8

Science. 2026 Jul 23. 393(6809): eadx0673

Human body single-cell atlas of three-dimensional genome organization and DNA methylation.

Higher-order chromatin structure and DNA methylation are critical for gene regulation, but how these vary across the human body remains unclear. We performed multiomic profiling of three-dimensional (3D) genome structure and DNA methylation for 86,689 single nuclei across 16 tissues, identifying 35 major and 206 cell subtypes. We revealed extensive changes in CG and non-CG methylation across cell types and characterized 3D chromatin structure at an unprecedented cellular resolution. Extensive discrepancies exist between cell types delineated by DNA methylation and genome structure, which indicates that the role of distinct epigenomic features in maintaining cell identity may vary by lineage. This study expands our understanding of the diversity of DNA methylation and chromatin structure and offers a reference for exploring gene regulation in human health and disease.

DOI: https://doi.org/10.1126/science.adx0673