Our findings indicate that cancer cells in the high ST6GAL1 expression group interact with M1 macrophages, Breg, and CD8+ T cells via HEBP1−EGFR, YARS−EGFR, and ICAM1−EGFR, suggesting that CRC patients with high ST6GAL1 expression may benefit from anti‐EGFR therapy. Here, CD8A is linked to colorectal carcinoma.