Background

Efforts to control cell death in cancer treatment have continued relentlessly. Conventional chemotherapeutics primarily induce apoptosis by causing genomic damage or inhibiting specific protein activities. However, cancer cells increasingly evade these death signals over time, acquiring strong resistance. The abnormal survival capacity of cancer cells within the tumor microenvironment is a major cause of treatment failure.

Recently, RNA modifications occurring after genetic information translation, known as epitranscriptomics, have been implicated as underlying mechanisms of cancer cell survival. This phenomenon involves chemical changes at the RNA level that regulate protein expression without altering the DNA sequence. Until now, research has largely focused on transcription factors and epigenetic DNA methylation, limiting the understanding of chemical post-transcriptional modifications in RNA molecules. In particular, to elucidate how cancer cells neutralize ferroptosis or conventional cell death pathways, a detailed analysis of these RNA modifications is essential.

Key Findings

Recent academic reports have experimentally confirmed that epitranscriptomic modifications directly regulate the threshold of cancer cell death. Five key chemical modifications—N⁶-methyladenosine (m⁶A), 5-methylcytosine (m⁵C), N⁷-methylguanosine (m⁷G), pseudouridylation (Ψ), and adenosine-to-inosine (A-to-I) editing—play central roles in these mechanisms.

The most frequently observed modification, m⁶A, does not act unidirectionally but produces contrasting outcomes depending on the ratio of reader proteins and their intracellular localization. For example, it can promote the expression of BCL-2 family proteins, yet simultaneously regulate the translation speed of the SLC7A11-GPX4 axis to hinder ferroptosis. These opposing effects reflect the cancer cell's ability to adjust expression patterns in response to stress.

The remaining four modifications also contribute to the formation of a defensive barrier in cancer cells. m⁵C modification has been shown to promote the synthesis of resistance proteins that counteract ferroptotic death signals. A-to-I editing, primarily mediated by ADAR (adenosine deaminase acting on RNA) enzymes, helps cancer cells evade immune surveillance by disguising mutant proteins as normal. Additionally, m⁷G modification and pseudouridylation provide pathways to maintain survival by activating the translation of survival proteins.

These chemical changes interact with microenvironmental stressors such as hypoxia and reactive oxygen species (ROS). Upon detection of external signals, regulatory enzymes become activated. Consequently, cancer cells adapt to harsh environments and develop resistance to existing therapies.

Implications and Prospects

Clarifying epitranscriptomic modifications represents a strategic milestone in overcoming chemotherapy resistance. Small-molecule compounds targeting RNA modification enzymes are actively being investigated as potential candidates. By eliminating the causes of chemoresistance and lowering the apoptosis threshold in cancer cells, the efficacy of existing therapies can be maximized.

Technical challenges must also be overcome for clinical translation. Technologies such as methylated RNA immunoprecipitation sequencing (MeRIP-seq) and nanopore sequencing exhibit resolution limitations in identifying modification sites at the single-molecule level. Quantitative stoichiometric analysis of individual RNA strands is also challenging. Additionally, toxicity arising from the broad inhibition of methylation enzymes remains a concern. If modifications in specific target genes cannot be selectively controlled, protein synthesis in normal cells may be impaired, leading to severe side effects.