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Inhibition of ALG3 stimulates cancer cell immunogenic ferroptosis to potentiate immunotherapy

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Abstract

Immune checkpoint blockade therapy has drastically improved the prognosis of certain advanced-stage cancers. However, low response rates and immune-related adverse events remain important limitations. Here, we report that inhibiting ALG3, an a-1,3-mannosyltransferase involved in protein glycosylation in the endoplasmic reticulum (ER), can boost the response of tumors to immune checkpoint blockade therapy. Deleting N-linked glycosylation gene ALG3 in mouse cancer cells substantially attenuates their growth in mice in a manner depending on cytotoxic T cells. Furthermore, ALG3 inhibition or N-linked glycosylation inhibitor tunicamycin treatment synergizes with anti-PD1 therapy in suppressing tumor growth in mouse models of cancer. Mechanistically, we found that inhibiting ALG3 induced deficiencies of post-translational N-linked glycosylation modification and led to excessive lipid accumulation through sterol-regulated element-binding protein (SREBP1)-dependent lipogenesis in cancer cells. N-linked glycosylation deficiency-mediated lipid hyperperoxidation induced immunogenic ferroptosis of cancer cells and promoted a pro-inflammatory microenvironment, which boosted anti-tumor immune responses. In human subjects with cancer, elevated levels of ALG3 expression in tumor tissues are associated with poor patient survival. Taken together, we reveal an unappreciated role of ALG3 in regulating tumor immunogenicity and propose a potential therapeutic strategy for enhancing cancer immunotherapy.

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Availability of data and materials

The data sets generated correlations between ferroptosis and immune gene expression profile during the current study are available in the public RNA sequencing data from NCBI Gene Expression Omnibus (accession number: GSE128392) All other data generated or analyzed during this study are included in this published article and its supplementary information files.

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Funding

This work was supported by Guangdong Basic and Applied Basic Research Foundation Grant (2020B1515020054), and Shenzhen Science and Technology Program Grant (JCY20190807154813511).

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Authors and Affiliations

  1. The Department of Biochemistry and Molecular Cell Biology, Molecular Cancer Research Center, School of Medicine, Sun Yat-Sen University, No. 66, Gongchang Rd, Shenzhen, 518107, Guangdong, China

    Pei Liu, Cha Lin, Zheyu Liu, Chenchen Zhu, Zhongda Lin, Dan Xu, Jian Chen, Linlin Hou, Ji-An Pan & Xinjian Liu

  2. Molecular Diagnostic Laboratory of Cancer Center, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Qian Huang

  3. Department of Dermatology, Duke University Medical Center, Durham, NC, USA

    Chuan-Yuan Li

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  1. Pei Liu
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  2. Cha Lin
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  3. Zheyu Liu
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  4. Chenchen Zhu
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Contributions

Conception and design: XL, CL. Development of methodology: PL, CL, JC, QH, J-AP. Acquisition of data: PL, CL, ZL, CZ, DX, ZL, LH. Writing, review, and/or revision of the manuscript: XL, PL. Study supervision: XL.

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Correspondence to Xinjian Liu.

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All animal experiment protocols were approved by the Sun Yat-sen University Institutional Animal Use and Care Committee.

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Liu, P., Lin, C., Liu, Z. et al. Inhibition of ALG3 stimulates cancer cell immunogenic ferroptosis to potentiate immunotherapy. Cell. Mol. Life Sci. 79, 352 (2022). https://doi.org/10.1007/s00018-022-04365-4

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