Tumor Intrinsic METTL5 Modulates ATF4 Translation to Prevent T Cell-Induced Ferroptosis in Ovarian Cancer

Jiakai Hou¹, Cheng-Wei Ju^{2

3

4}, Nicholas A Egan¹, Yanjun Wei⁵, Yunfei Wang⁶, Minghao Dang⁷, Tianyi Zhou¹, Leilei Shi⁸, Ningbo Zheng¹, Si Chen¹, Ashley M Guerrero¹, Xiaofang Liang¹, Wanfu Wu¹, Areej Akhtar¹, Chitra Dhiman¹, Debanwita Roy Burman¹, Andro E Gerges¹, Mason D Flores¹, Han Li^{2

3}, Li-Sheng Zhang², Marleen Kok^{9

10}, Xiaobo Mao¹¹, Linghua Wang¹², Qin Feng¹, Yiwen Chen^{5

13}, Sanghoon Lee¹⁴, Daniel J McGrail¹⁵, Nidhi Sahni^{5

8}, Chuan He^{2

3

16

17}, Amir A Jazaeri¹⁴, Weiyi Peng¹

Affiliations

¹ Department of Biology and Biochemistry, University of Houston, Houston, TX, 77204, USA.
² Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA.
³ Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, 60637, USA.
⁴ Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL, 60637, USA.
⁵ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁶ Clinical Science Lab, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.
⁷ Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁸ Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁹ Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
¹⁰ Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
¹¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21218, USA.
¹² Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹³ Quantitative Sciences Program, The University of Texas MD Anderson Cancer Center, UT Health Graduate School of Biomedical Sciences, Houston, TX, USA.
¹⁴ Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹⁵ Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, 44195, USA.
¹⁶ Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, 60637, USA.
¹⁷ Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, 60637, USA.

PMID: 41042068
DOI: 10.1002/advs.202507718

Tumor Intrinsic METTL5 Modulates ATF4 Translation to Prevent T Cell-Induced Ferroptosis in Ovarian Cancer

Jiakai Hou et al. Adv Sci (Weinh). 2025.

. 2025 Oct 3:e07718.

doi: 10.1002/advs.202507718. Online ahead of print.

Authors

Affiliations

¹ Department of Biology and Biochemistry, University of Houston, Houston, TX, 77204, USA.
² Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA.
³ Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, 60637, USA.
⁴ Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL, 60637, USA.
⁵ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁶ Clinical Science Lab, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.
⁷ Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁸ Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁹ Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
¹⁰ Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
¹¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21218, USA.
¹² Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹³ Quantitative Sciences Program, The University of Texas MD Anderson Cancer Center, UT Health Graduate School of Biomedical Sciences, Houston, TX, USA.
¹⁴ Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹⁵ Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, 44195, USA.
¹⁶ Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, 60637, USA.
¹⁷ Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, 60637, USA.

PMID: 41042068
DOI: 10.1002/advs.202507718

Abstract

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 m⁶A 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.

Keywords: ATF4; CRISPR screen; METTL5; ferroptosis; immunotherapy; ovarian cancer.

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Tumor Intrinsic METTL5 Modulates ATF4 Translation to Prevent T Cell-Induced Ferroptosis in Ovarian Cancer

Affiliations

Tumor Intrinsic METTL5 Modulates ATF4 Translation to Prevent T Cell-Induced Ferroptosis in Ovarian Cancer

Authors

Affiliations

Abstract

References

Grants and funding

LinkOut - more resources

Research Materials