Targeting Cancer Translational Plasticity: IRES-Driven Metabolism and Survival Within the Tumor Microenvironment

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.