Abstract

Under hypoxic conditions, tumour cells engage in autophagic secretion of mitochondria to sustain energy balance and modulate the tumour microenvironment. However, the exact molecular mechanisms remain unclear. This study used a combination of multivesicular bodies membrane proteomics and molecular interaction validation to demonstrate that hypoxia promotes mitophagy-dependent extracellular vesicles (EVs) secretion in head and neck squamous cell carcinoma (HNSCC). This process promotes tumour-associated macrophages to adopt immunosuppressive phenotypes, reshaping the immune environment. Vesicle-associated membrane protein 4 (VAMP4) and syntaxin 8 (STX8) are key molecules involved in this secretion. Clinically, VAMP4/STX8 expressions are significantly higher in HNSCC than in normal tissues and correlate with prognosis, indicating their potential as biomarkers and therapeutic targets. This study revealed the mitophagy-secretion axis that reshaped the tumour immune landscape, providing a theoretical basis for targeting soluble NSF attachment protein receptor-dependent EV release to enhance the therapeutic effect of HNSCC immunotherapy.