In conclusion, we have revealed the modification of AnxA6 by SUMO1 conjugation to escalate its functions especially involving in dephosphorylation of EGFR-ERK1/2 signaling, and AnxA6 SUMOylation at K299 residue facilitates the binding of PKCα to EGFR and subsequently impedes EGFR activity, thereby inhibiting cell proliferation, migration, and the xenograft tumor growth of epithelial cancer cells, as well as improving gefitinib drug sensitivity. Here, EGFR is linked to neoplasm.