Taken together, our findings reveal a novel mechanism by which TAR RNA-bearing exosomes enter into recipient cancer cells via EGFR, resulting in activation of the ERK1/2 cascade and expression of proto-oncogenes and ISGs through interaction with EGFR and TLR3, leading to enhanced growth and progression of NADCs, such as HNSCC and lung cancer. Here, TLR3 is linked to head and neck squamous cell carcinoma.