Ferroptosis, an iron-dependent form of regulated cell death, is increasingly recognized as a context-dependent therapeutic vulnerability in cancer, particularly as malignant cells adapt to oxidative, metabolic, and therapy-induced stresses. As a prevalent and reversible epitranscriptomic modification, RNA N6-methyladenosine (m6A) modification orchestrates RNA stability, translation, splicing and decay; consequently, its dysregulation contributes to cancer progression and therapeutic resistance. The intersection of m6A regulation and ferroptosis is therefore biologically important because many ferroptosis threshold genes are short-lived, stress-responsive transcripts controlled by writers, erasers, readers and RNA-binding proteins. This review synthesizes empirical evidence elucidating how m6A regulators remodel cystine import, GPX4-dependent antioxidant defense, FSP1 signaling, lipid metabolism, iron handling, autophagy and tumor-microenvironmental communication. We organize the evidence by regulatory layer rather than cancer type, covering writer-mediated deposition, reader and RNA-binding protein recognition, eraser-dependent demethylation, non-coding RNA and exosomal regulation, and downstream ferroptosis modules. We further discuss how this axis contributes to radiotherapy, chemotherapy, targeted-therapy resistance and ferroptosis-sensitizing combinations. Although m6A-ferroptosis crosstalk offers promising biomarker and therapeutic opportunities, translation requires transcript-level validation, standardized ferroptosis assays, tumor-selective delivery and clinically meaningful patient stratification. A deeper and more precise integration of epitranscriptomics with ferroptosis biology holds the potential to transform stress-adaptive RNA circuits into actionable vulnerabilities for precision cancer therapy.
Qing-Miao Shi, Yang-Ni Li, Chao Guan· Frontiers in Cell and Develo...· 0 citations
INTRODUCTION
The important roles of T cells in tumor progression support the development of a T cell-associated prognostic model for Head and Neck Squamous Cell Carcinoma (HNSCC).
METHODS
The single-cell RNA-seq (scRNS-seq) data from GSE181919 were processed via the Seurat package for quality control and cell annotation. hdWGCNA was used to identify T cell-associated co-expression modules. Key genes were screened by univariate and LASSO Cox regression in TCGA to build a RiskScore model, followed by validation in the GSE41613 and GSE117973 datasets. The correlations of the RiskScore with the immune microenvironment, predicted immunotherapy response, and drug sensitivity were analyzed, and preliminary in vitro assays were conducted to explore PIM2 function in HNSCC cells.
RESULTS
Ten cell populations were identified in HNSCC tissues, with T cells representing one of the major cell populations. An eight-gene RiskScore model (TNFRSF4, TNFRSF18, PIM2, CORO1B, CUL9, SOD1, ZC3H12D, and TUBA1B) was established, showing moderate but significant prognostic value. High-risk patients exhibited significantly poorer survival. A nomogram integrating the RiskScore and clinical features was further constructed. Additional analyses supported the prognostic value of the model in HPV-negative patients and showed that the RiskScore was independently associated with overall survival after adjustment for tumor purity. C-index comparisons further revealed higher and relatively consistent prognostic discrimination compared with two previously published HNSCC models. The high-risk group exhibited lower ImmuneScore, StromalScore, ESTIMATEScore, higher TIDE scores, and reduced immune infiltration. The RiskScore was significantly correlated with 11 candidate compounds, and preliminary in vitro assays showed that PIM2 knockdown suppressed malignant phenotypes of HNSCC cells.
DISCUSSION
The scRNS-seq and hdWGCNA analyses identified eight T cell-associated module genes related to HNSCC prognosis. High- and low-risk patients stratified by the RiskScore exhibited distinct immune infiltration and angiogenesis in their Tumor Microenvironment (TME). Drug sensitivity analysis predicted candidate compounds for HNSCC treatment, but further experimental and clinical validation is required.
CONCLUSION
The T cell-associated prognostic model was associated with immune microenvironment features and predicted treatment response and may help predict HNSCC prognosis, providing candidate biomarkers for further investigation.
Qing-miao Shi, Zhen-Zhen Qi, Bingyang Shang et al.· Current Medicinal Chemistry· 0 citations
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, Yuting 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.
This review systematically consolidates recent advances in understanding how lncRNAs precisely modulate Notch pathway activity through diverse mechanisms, including acting as competing endogenous RNAs, direct protein binding, epigenetic regulation, and exosome-mediated intercellular communication.
Qing-Miao Shi, Na Lou, Huiwu Xing et al.· Frontiers in Cell and Develo...· 0 citations
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