5-Methylcytosine RNA modification and its roles in cancer and cancer chemotherapy resistance.

Recent advancements in cancer therapies have improved clinical outcomes, yet therapeutic resistance remains a significant challenge because of its complex mechanisms. Among epigenetic factors, m5C RNA modification is emerging as a key player in cancer drug resistance, similar to the well-known m6A modification. m5C affects RNA metabolism processes, including splicing, export, translation, and stability, thereby influencing drug efficacy. This review highlights the critical roles of m5C in modulating resistance to chemotherapy, targeted therapy, radiotherapy, and immunotherapy. This review also discusses the functions of key regulators, including methyltransferases, demethylases, and m5C-binding proteins, as essential modulators of the m5C epigenetic landscape that contribute to its dynamic and complex regulatory network. Targeting these regulatory components offers a promising strategy to overcome resistance. We highlight the need for further research to elucidate the specific mechanisms by which m5C contributes to resistance and to develop precise m5C-targeted therapies, presenting m5C-focused strategies as potential novel anticancer treatments.