ANO1‐Mediated Inhibition of Cancer Ferroptosis Confers Immunotherapeutic Resistance through Recruiting Cancer‐Associated Fibroblasts

The application of immunotherapy in gastrointestinal (GI) cancers remains challenging because of the limited response rate and emerging therapeutic resistance. Combining clinical cohorts, multi‐omics study, and functional/molecular experiments, it is found that ANO1 amplification or high‐expression predicts poor outcomes and resistance to immunotherapy for GI cancer patients. Knocking‐down or inhibiting ANO1 suppresses the growth/metastasis/invasion of multiple GI cancer cell lines, cell‐derived xenograft, and patient‐derived xenograft models. ANO1 contributes to an immune‐suppressive tumor microenvironment and induces acquired resistance to anti‐PD‐1 immunotherapy, while ANO1 knockdown or inhibition enhances immunotherapeutic effectiveness and overcomes resistance to immunotherapy. Mechanistically, through inhibiting cancer ferroptosis in a PI3K‐Akt signaling‐dependent manner, ANO1 enhances tumor progression and facilitates cancer‐associated fibroblast recruitment by promoting TGF‐β release, thus crippling CD8(+) T cell‐mediated anti‐tumor immunity and generating resistance to immunotherapy. This work highlights ANO1's role in mediating tumor immune microenvironment remodeling and immunotherapeutic resistance, and introduces ANO1 as a promising target for GI cancers’ precision treatment.