Through unveiling the existence of an ANO1‐PI3K‐Akt‐ferroptosis‐CAF regulative axis, our work outlined the functional details of ANO1 in mediating tumor progression and TIME remodeling, provided clues for GI cancers’ low effectiveness/resistance to immunotherapy, and introduced ANO1 as a promising target for anti‐cancer precision treatment. The gene discussed is PIK3CA; the disease is cancer.