The tumor microenvironment creates strong stress conditions, including hypoxia and nutrient depletion, which cause the blocking of cap-dependent translation. Under stressful conditions, cancer cells exploit the cap-independent translation mechanism mediated by internal ribosome entry site (IRES), which ensures continued protein synthesis. IRES elements located in the 5′ untranslated regions of specific mRNAs allow selective translation of key anti-apoptotic and adaptive proteins. These proteins promote cellular processes that sustain cell survival, among them metabolic reprogramming, redox balance, and epithelial-to-mesenchymal transition, thus facilitating tumor progression and therapy resistance. IRES activity is dynamically regulated by IRES trans-acting factors, such as YB-1, PTB, and hnRNPA1, which respond to cellular stress by enhancing translation of crucial mRNAs. Emerging therapeutic strategies include pharmacological IRES inhibitors, RNA-based approaches targeting ITAF interactions, and IRES-containing vectors for controlled therapeutic gene expression. A deeper understanding of translational reprogramming, IRES structural diversity, and ITAF function is essential to develop targeted interventions to overcome therapeutic resistance and eliminate persistent tumor cell populations.
肿瘤微环境会形成强烈的应激条件，包括缺氧和营养耗竭，这些条件导致帽依赖性翻译受阻。在应激条件下，癌细胞利用由内部核糖体进入位点（IRES）介导的帽非依赖性翻译机制，确保蛋白质合成的持续进行。位于特定mRNA 5′非翻译区的IRES元件能够选择性翻译关键的抗凋亡和适应性蛋白。这些蛋白促进维持细胞存活的相关细胞过程，包括代谢重编程、氧化还原平衡以及上皮-间质转化，从而推动肿瘤进展并产生治疗抵抗。IRES活性受IRES反式作用因子（如YB-1、PTB和hnRNPA1）的动态调控，这些因子通过增强关键mRNA的翻译来响应细胞应激。新兴的治疗策略包括药物性IRES抑制剂、靶向ITAF相互作用的RNA干预方法，以及用于可控治疗基因表达的IRES载体系统。深入理解翻译重编程机制、IRES结构多样性及ITAF功能，对于开发靶向干预措施以克服治疗抵抗并清除持续性肿瘤细胞群体至关重要。
肿瘤(癌症)患者之家