Tumor Intrinsic METTL5 Modulates ATF4 Translation to Prevent T Cell‐Induced Ferroptosis in Ovarian Cancer
Poor clinical responses to immune checkpoint blockade (ICB) observed in ovarian cancer (OC) highlight an unmet need to understand the mechanisms driving immune evasion in this disease. To address this, an integrative analysis is conducted by combining in vitro genome-wide immune screens, in vivo ICB screens, and clinical data mining, and METTL5 is identified as a crucial OC-intrinsic factor that promotes immune resistance. Immunologically "cold" OC tumors and poor responders to ICB exhibit elevated METTL5 expression. Mechanistically, knocking out (KO) METTL5 in OC disrupts ATF4 translation by altering 18S rRNA m<sup>6</sup>A levels, leading to the downregulation of SLC7A11 and SLC3A2, whose function is to suppress ferroptosis activity. Consequently, METTL5 KO enhances tumor sensitivity to T cell-mediated antitumor immunity. Notably, the immune-sensitive phenotypes seen in METTL5-KO tumors can be reversed by either ATF4 overexpression or ferroptosis inhibition. These findings underscore the central role of the METTL5/ATF4/ferroptosis axis in controlling OC responses to immunotherapy.
Authors
- Amir A. Jazaeri (ORCID: https://orcid.org/0000-0003-4335-4151)
- Lisheng Zhang (ORCID: https://orcid.org/0000-0003-1872-9978)
- Jiakai Hou (ORCID: https://orcid.org/0000-0003-2875-8756)
- Cheng‐Wei Ju (ORCID: https://orcid.org/0000-0002-2250-8548)
- Xiaobo Mao (ORCID: https://orcid.org/0000-0001-6587-556X)
- Amany Nagy Abdalla Gerges
- Debanwita Roy Burman (ORCID: https://orcid.org/0000-0002-3352-5052)
- Qin Fu Feng (ORCID: https://orcid.org/0000-0002-4257-8404)
- Ningbo Zheng (ORCID: https://orcid.org/0000-0002-3684-5596)
- Linghua Wang (ORCID: https://orcid.org/0000-0001-9380-0266)
- Ashley Guerrero (ORCID: https://orcid.org/0009-0008-6393-9433)
- Yanjun Wei (ORCID: https://orcid.org/0000-0003-4200-2859)
- Daniel James McGrail (ORCID: https://orcid.org/0000-0002-6669-6069)
- Nidhi Sahni (ORCID: https://orcid.org/0000-0002-9155-5882)
- Minghao Dang (ORCID: https://orcid.org/0000-0001-7287-2877)
- Marleen Kok (ORCID: https://orcid.org/0000-0001-9043-9815)
- Weiyi Peng (ORCID: https://orcid.org/0000-0002-7785-6240)
- Areej Akhtar
- Tianyi Zhou (ORCID: https://orcid.org/0009-0002-1058-8218)
- Xiaofang Liang (ORCID: https://orcid.org/0009-0009-9117-8325)
- María Elena Flores (ORCID: https://orcid.org/0000-0001-8591-1855)
- Chuan He (ORCID: https://orcid.org/0000-0003-4319-7424)
- Sanghoon Lee (ORCID: https://orcid.org/0000-0001-8564-2392)
- Si Chen (ORCID: https://orcid.org/0000-0002-9716-9966)
- Yunfei Wang (ORCID: https://orcid.org/0009-0000-4928-6853)
- Yiwen Chen (ORCID: https://orcid.org/0000-0002-7706-7540)
- Li Han (ORCID: https://orcid.org/0000-0002-4486-0534)
- Leilei Shi (ORCID: https://orcid.org/0000-0001-6833-8196)
- Wanfu Wu (ORCID: https://orcid.org/0000-0002-2231-9528)
- Nicholas A. Egan (ORCID: https://orcid.org/0009-0003-7662-9817)
- Chitra Dhiman
Institutions
- Cleveland Clinic (US)
- The University of Texas MD Anderson Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- Chicago Institute for Psychoanalysis (US)
- Johns Hopkins Medicine (US)
- Moffitt Cancer Center (US)
- University of Chicago (US)
- Oncode Institute (NL)
- University of Houston (US)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-10-03
- DOI
- https://doi.org/10.1002/advs.202507718
- Citations
- 2
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Cancer Prevention and Research Institute of Texas
- Gilead Sciences
- Ludwig Institute for Cancer Research
- Andrew Sabin Family Foundation
- Ovarian Cancer Research Alliance
- MacroGenics
- Eisai
- Genentech
- Daiichi Sankyo Europe