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


ABSTRACT: 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.

SUBMITTER: Jiang F 

PROVIDER: S-EPMC10460848 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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

Jiang Fangli F   Jia Keren K   Chen Yang Y   Ji Congcong C   Chong Xiaoyi X   Li Zhongwu Z   Zhao Feilong F   Bai Yuezong Y   Ge Sai S   Gao Jing J   Zhang Xiaotian X   Li Jian J   Shen Lin L   Zhang Cheng C  

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20230621 24


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  ...[more]

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