In this study, through performing comprehensive investigations with GI cancer patient cohorts, bioinformatics datasets, and in vitro/in vivo models, we discovered ANO1 suppresses cancer ferroptosis in a PI3K‐Akt signaling‐dependent manner, thus facilitating CAF recruitment through promoting TGF‐β release, subsequently compromising CD8+ T cell‐mediated anti‐tumor immunity and inducing resistance to immunotherapy. This evidence concerns the gene PIK3CA and cancer.