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, MAPK3 is linked to lung cancer.