Nucleoside antitumor drugs: From molecular mechanisms and adaptive resistance to clinical translation

Nucleoside-based anticancer drugs are still needed to treat solid tumours and blood cancers, but due to systemic toxicity and the emergence of resistance, they have performed poorly in clinical practice. These agents inhibit deoxyribonucleic acid (DNA) synthesis, disrupt ribonucleic acid (RNA) metabolism, or deplete nucleotide pools in the past. However, a large number of studies have also found that the pharmacological effects of these agents include replication stress, epigenetic modification, viral mimicry and immunogenic cell death , as well as direct damage to nucleic acids. At the same time, resistance to nucleoside-based therapy is now known to be a system-level adaptation phenomenon. This resistance network includes impaired nucleoside transport, altered kinase-dependent activation, increased catabolism by enzymes such as cytidine deaminase (CDA) and sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1), compensatory DNA damage repair, immune suppression, and microbiome-mediated drug inactivation in the tumour ecosystem. We will introduce the molecular mechanisms and multi-level resistance networks of nucleoside-type anticancer drugs in this paper, and based on the obtained results, put forward new therapeutic strategies. Particular emphasis is placed on phosphoramidate prodrug (ProTide) technology, multivalent oligonucleotide prodrugs, nanocarrier-mediated delivery and mechanism-guided combination therapy. We will also introduce the new applications of antibody-based delivery systems for tumour-selective delivery. According to the tumour's biology and drug-metabolism properties, delivery science and biomarker-guided therapy can be employed to convert nucleoside-based therapy into a form of personalised medicine that overcomes adaptive resistance.