SHISA3, a member of the SHISA family,[19] is a transmembrane protein that has been reported to inhibit the Wnt/β‐catenin signaling pathway and functions as a tumor suppressor.[20, 21] Hypermethylation of SHISA3 promoter occurs in a variety of tumors, including breast cancer, (BC)[22] colorectal cancer (CRC),[23] nasopharyngeal cancer (NPC),[24] and lung adenocarcinoma (LUAD).[25, 26] However, its role in immune cells, including macrophages, is not yet revealed. This evidence concerns the gene SHISA3 and colorectal cancer.