LAUSR

Abstract Research on tumour cell‐derived small extracellular vesicles (sEVs) that regulate tumour microenvironment (TME) has provided strategies for targeted therapy of head and neck squamous cell carcinoma (HNSCC). Herein, we demonstrated that sEVs derived from HNSCC cancer cells carried CD73 (sEVsCD73), which promoted malignant progression and mediated immune evasion. The sEVsCD73 phagocytosed by tumour‐associated macrophages (TAMs) in the TME induced immunosuppression. Higher CD73high TAMs infiltration levels in the HNSCC microenvironment were correlated with poorer prognosis, while sEVsCD73 activated the NF‐κB pathway in TAMs, thereby inhibiting immune function by increasing cytokines secretion such as IL‐6, IL‐10, TNF‐α, and TGF‐β1. The absence of sEVsCD73 enhanced the sensitivity of anti‐PD‐1 therapy through reversed immunosuppression. Moreover, circulating sEVsCD73 increased the risk of lymph node metastasis and worse prognosis. Taken together, our study suggests that sEVsCD73 derived from tumour cells contributes to immunosuppression and is a potential predictor of anti‐PD‐1 responses for immune checkpoint therapy in HNSCC.