N6-methyladenosine (m6A), as the most abundant epitranscriptomic modification in eukaryotes, profoundly influences the metabolic fate of RNA. Meanwhile, ferroptosis, a regulated cell death modality driven by iron-dependent lipid peroxidation, has become a key component in tumor metabolic reprogramming. Increasing evidence suggests a deep interaction between m6A modification and ferroptosis, which plays a critical role in tumor occurrence and development, and treatment response. This review systematically elucidates the multidimensional regulatory mechanisms of m6A on ferroptosis regulatory factors, covering post-transcriptional modifications of the System Xc
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/GSH/GPX4 antioxidant axis, iron metabolism-related proteins, and key enzymes of lipid peroxidation. It analyzes the dual role of the m6A-ferroptosis axis in tumor suppression and promotion, and then explores the function of this regulatory network in reshaping the tumor immune microenvironment and mediating treatment resistance. Finally, it looks forward to the translational potential of the m6A-ferroptosis interactive network as a novel biomarker and combination therapy target. Future research should integrate multi-omics and cutting-edge technologies to deeply analyze the spatiotemporal dynamic mechanism of this regulatory network in the occurrence and development of tumors, providing theoretical basis and new research directions for precise intervention in this interdisciplinary field.
Yu-Shuo Duan, Zi-Yi Xu, Jia-Hao Liang et al.· Frontiers in Cell and Develo...· 0 citations
Hepatocellular carcinoma (HCC), a malignancy with high global morbidity and mortality, has therapeutic resistance as a major focus of both clinical and basic research. In recent years, protein post-translational modifications (PTMs), key regulators of intracellular protein function and cell signaling, play critical roles in therapeutic resistance in liver cancer. Current studies indicate that diverse PTMs—including phosphorylation, ubiquitination, acetylation, lactylation, and glycosylation—modulate liver cancer cell responses to chemotherapy, targeted therapy, immunotherapy and local therapies. This review systematically summarizes the molecular mechanisms and common pathways through which PTMs contribute to therapeutic resistance in liver cancer, explores PTM-mediated mechanism underlying tumor persistence and distant recurrence,examines how PTM-targeted strategies may reverse resistance, and discusses the challenges and prospects of these therapeutic approaches in clinical practice. By integrating current research, this review aims to provide a theoretical basis and potential targets for precision therapy of drug-resistant liver cancer, offering novel intervention targets and translational strategies to overcome therapeutic resistance in HCC.
Si-Min Feng, Jie Hu, Xiao-Xi Guo et al.· Frontiers in Immunology· 0 citations
ABSTRACT Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths, its progression and treatment heterogeneity are mainly influenced by driver gene and tumor micro-environment (TME) interactions. Nevertheless, the mechanisms of this process at the single-cell level remain unclear. This study integrated TCGA and multi-center single-cell transcriptome data to identify a 575 genes HCC-specific core set, developing a single-cell “oncogene scoring” system to quantify individual carcinogenic activity. This score is significantly elevated in malignant and proliferative T cells and is closely associated with metabolic reprogramming, aberrant cell‒cell communication, and immunosuppressive phenotypes. Based on these characteristics, we constructed a machine learning-based Random Survival Forest (RSF) prognostic model validated in multiple independent cohorts, which classifies patients into distinct risk subtypes. The high-risk group exhibits genomic instability, increased tumor stemness, and immune evasion, while the low-risk group was more sensitive to drugs such as sorafenib. This study highlights the potential pathways by which high oncogenic activity is associated with HCC progression, suggesting a profound link with single-cell metabolic‒immune crosstalk. The constructed RSF model offers a promising computational framework for risk stratification and provides hypothesis-generating insights that may inform future personalized treatment strategies for HCC patients.
Cancer immunotherapy has revolutionized the landscape of cancer treatment, particularly through the development of immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis. However, the therapeutic efficacy of these interventions is frequently hindered by the immunosuppressive tumor microenvironment (TME), which is characterized by hypoxia, poor immune cell infiltration, and impaired antigen presentation. To overcome these barriers, MP-GCZ has been developed as a self-oxygenating biomimetic nanomotor to synergistically reprogram the TME and enhance antitumor immune responses through integrated multimodal mechanisms. This nanosystem combines photothermal therapy (PTT), cuproptosis-induced immunogenic cell death (ICD), and localized immune checkpoint modulation to address the complex immunosuppressive network of the TME. By leveraging a metal-organic framework scaffold, MP-GCZ enables controlled delivery of therapeutic components that alleviate hypoxia, trigger immunogenic tumor cell death, and enhance adaptive immune responses. When activated by near-infrared irradiation, MP-GCZ enhances dendritic cell maturation, increases infiltration of cytotoxic T lymphocytes, thereby transforming immunologically "cold" tumors into inflamed, immunogenic environments. Preclinical studies demonstrate that this strategy effectively suppresses both primary tumor growth and distant metastases, driven by systemic antitumor immunity. MP-GCZ represents a promising comprehensive approach to overcoming TME-mediated resistance and may offer a valuable solution to enhance the clinical efficacy of cancer immunotherapy.
Xin-yu Gu, Sheng-Wei Shen, Yu-Ting He et al.· Materials Today Bio· 0 citations
This review critically synthesizes the multifaceted roles of RNA modifications to bridge the gap between descriptive epitranscriptomic mapping and functional tumor biology, and aims to facilitate the translation of epitranscriptomic findings into clinical applications.
