Decoding the ubiquitin network: molecular mechanisms and therapeutic vulnerabilities for precision radio-sensitization in cancer

Abstract

Radiotherapy resistance remains a major clinical challenge, largely driven by tumors’ ability to dynamically adapt through complex molecular networks. Critically, the ubiquitin system has emerged as a critical regulator of this resistance. This review examines how the ubiquitin system orchestrates radiotherapy resistance through spatiotemporal control of DNA repair fidelity, metabolic reprogramming, and immune evasion. We explore how the ubiquitin code, defined by its chain topology diversity (such as K48-linked proteolysis versus K63-mediated signaling) and crosstalk with phosphorylation, SUMOylation, and acetylation, generates diverse resistance mechanisms. These mechanisms, however, also present vulnerabilities exploitable for radio-sensitization. Notably, monoubiquitylation of both histone and non-histone protein collaboratively modulates chromatin dynamics and DNA damage responses to maintain genome integrity during radiation. Furthermore, ubiquitination critically regulates caner metabolism, reprogramming processes such as ferroptosis susceptibility, hypoxia adaptation, and nutrient flux, thereby creating targetable vulnerabilities for radio-sensitization. While targeting key E3 ligases and deubiquitinases (DUBs) shows preclinical promise, clinical translation faces obstacles including functional redundancy, unintended on-target toxicity, and adaptive tumor responses. Distinct from other post-translational modifications (PTMs), the ubiquitin system offers unique clinical advantages: its dynamic reversibility, chain topology diversity, and recent breakthroughs in targeted degradation (e.g., PROTACs) enable precise disruption of radioresistance networks. By integrating these mechanistic insights with biomarker-guided therapeutic strategies, ubiquitin-targeting agents are emerging as fundamental components of next-generation radiotherapy protocols.