# Chromatin Accessibility in Cancer: Biological Functions, Mechanisms, Therapeutic Potential, and Future Directions

## TL;DR

This review explores how chromatin accessibility influences cancer development and treatment, highlighting new strategies and technologies for precision oncology.

## Contribution

The paper systematically integrates chromatin accessibility with tumor biology and therapeutic strategies, which has been underexplored in prior reviews.

## Key findings

- Chromatin accessibility is regulated by genetic, epigenetic, and environmental factors and plays a key role in cancer progression and therapy resistance.
- Multiomics and AI integration offers novel perspectives for epigenetics-based precision tumor therapy.
- Current limitations in translating chromatin accessibility research into clinical applications are identified, along with future directions.

## Abstract

Cancer remains a major therapeutic challenge owing to its complex pathogenesis and the limitations of current treatments, such as poor specificity, toxicity, and multidrug resistance. Chromatin accessibility, which is dynamically regulated by genetic, epigenetic, and environmental factors, plays crucial roles in cancer initiation and progression. However, substantial obstacles persist in developing therapeutic strategies that target chromatin accessibility and translating them into clinical practice. This review comprehensively summarizes the biological functions and regulatory mechanisms of chromatin accessibility in tumors, encompassing tumorigenesis, progression, metabolic reprogramming, angiogenesis, stemness, tumor immune microenvironment, and therapy resistance. We integrate comparisons between human and murine models and detail key profiling technologies, including Assay for Transposase‑Accessible Chromatin with high‑throughput sequencing, DNase‑seq, single‑cell multiomics, and three‐dimensional chromatin‑conformation assays. Furthermore, we compile recent preclinical and clinical trials that utilize chromatin accessibility as a biomarker or therapeutic target, along with combination strategies involving chemotherapy, immunotherapy, targeted therapy, and radiotherapy. From a multiomics and interdisciplinary perspective, we discuss current limitations in translating fundamental research into clinical applications and highlight future directions for epigenetics‑based precision oncology.

Cancer remains the leading cause of mortality worldwide, and drug resistance further underscores the urgent need for innovative therapeutic strategies. Chromatin, a stable yet highly dynamic nucleoprotein complex, serves as the primary carrier of genetic material in eukaryotic cells. Chromatin accessibility reflects the degree of openness of chromatin structure, determining the capacity of DNA to interact with transcription factors, regulatory proteins, and other molecules. The dynamic relationship between chromatin accessibility and gene transcription activity represents a core mechanism of gene expression regulation. Regulated by multiple epigenetic mechanisms, chromatin accessibility has attracted significant research attention for its critical role in tumor initiation, progression, and treatment response.

Unlike previous reviews on chromatin accessibility, which primarily characterized its landscapes and regulatory mechanisms or its broad pathological roles in human diseases, a systematic integration of chromatin accessibility with tumor biology and therapeutic strategies remains underexplored. This review synthesizes the latest research to analyze the progress and limitations in current chromatin accessibility studies, comprehensively assessing the research landscape. We specifically focus on exploring: (1) the key epigenetic mechanisms governing chromatin accessibility during tumorigenesis and progression; (2) its functional impact in tumors; and (3) current key strategies and emerging technologies in tumor therapy, including a compiled list of representative epigenetic drugs based on different targets for cancer treatment and their associated clinical trials in combination therapies. We also explore the feasibility and novel perspectives of integrating multiomics approaches with artificial intelligence to advance epigenetics‐based precision tumor therapy.