Collectively, our work proved that the amplification/upregulation of ANO1 in GI cancers abolishes cancer ferroptosis in a PI3K‐Akt signaling‐dependent manner, consequently increases cancer cell survival and strengthens CAF recruitment through elevating TGF‐β release, and thus promotes tumor progression and cripples anti‐tumor immune responses, generating resistance to immunotherapy. Here, PIK3CA is linked to cancer.