Mannose and PMI depletion overcomes radiation resistance in HPV-negative head and neck cancer

Radiotherapy is critical component of multidisciplinary cancer care, used as a primary and adjuvant treatment for patients with head and neck squamous cell carcinoma. This study investigates how mannose, a naturally occurring monosaccharide, combined with phosphomannose isomerase (PMI) depletion, enhances the sensitivity of HPV-negative head and neck tumour models to radiation. Isogenic PMI knockout models were generated by CRISPR/Cas9 gene editing, yielding a 20-fold increase in sensitivity to mannose in vitro, and causing significant tumour growth delay in vivo. This effect is driven by metabolic reprogramming, resulting in potent glycolytic suppression coupled with consistent depletion of ATP and glycolytic intermediates in PMI-depleted models. Functionally, these changes impede DNA damage repair following radiation, resulting in a significant increase in radiation sensitivity. Mannose and PMI ablation supressed both oxygen consumption rate and extracellular acidification, pushing cells towards a state of metabolic quiescence, effects contributing to increased radiation sensitivity under both normoxic and hypoxic conditions. In 3D-tumoursphere models, metabolic suppression by mannose and PMI depletion was shown to elevate intra-tumoursphere oxygen levels, contributing to significant in vitro oxygen-mediated radiosensitisation. These findings position PMI as a promising anti-tumour target, highlighting the potential of mannose as a metabolic radiosensitiser enhancing cancer treatment efficacy.