RNA modifications as determinants of cancer cell death: from epitranscriptomic mechanisms to therapeutic targeting.

Epitranscriptomics has rapidly evolved into a central layer of post-transcriptional gene regulation in cancer, yet its mechanistic contribution to regulated cell death remains incompletely resolved. This review critically examines how RNA modifications principally N⁶-methyladenosine (m⁶A), alongside 5-methylcytosine (m5C), N⁷-methylguanosine (m⁷G), pseudouridylation (Ψ), and adenosine-to-inosine (A-to-I) editing reprogram apoptotic and ferroptotic thresholds in malignant cells. It highlights that m⁶A does not exert uniform effects; rather, outcomes are dictated by site specificity, reader stoichiometry, and cellular context, with opposing roles observed in the regulation of BCL-2 family signaling and the SLC7A11-GPX4 antioxidant axis. The analysis extends beyond m⁶A to evaluate emerging, yet often under-validated, evidence implicating m5C in ferroptosis resistance, A-to-I editing in immune evasion, and m⁷G/Ψ in translational control of survival programs. Importantly, the review integrates tumor microenvironmental pressures including hypoxia, reactive oxygen species, and immune signaling-as dynamic modulators of epitranscriptomic machinery, thereby linking RNA chemistry to adaptive stress responses and therapeutic resistance. Despite rapid technological advances, including MeRIP-seq, crosslinking-based mapping, and nanopore direct RNA sequencing, the field remains constrained by limited resolution, lack of quantitative stoichiometry, and insufficient site-specific functional validation. Many conclusions are derived from global perturbation of epitranscriptomic enzymes, obscuring causal attribution to individual modified transcripts. From a translational perspective, targeting writers, erasers, and readers offers promise for sensitizing tumors to cell death; however, pleiotropy, context dependency, and potential toxicity present significant barriers. Overall, this review argues that while epitranscriptomics represents a compelling regulatory axis in cancer cell death, advancing the field will require integrative, high-resolution, and functionally precise approaches to move beyond correlative frameworks toward mechanistic and clinically actionable insights.