Abstract To systematically define tumor-intrinsic mechanisms driving immune resistance in ovarian cancer (OC), we integrated an in vitro genome-wide CRISPR immune screen, in vivo targeted immune screens, and analysis of 16 published ICB patient cohorts. From this pipeline, 693 candidate genes were shortlisted, and METTL5 emerged as a key regulator of tumor-intrinsic immune evasion. Pan-cancer TCGA analysis revealed significant METTL5 upregulation across multiple cancer types, with OC showing the second-highest expression among 34 malignancies. Although METTL5 expression did not correlate with OC stage or overall survival, higher expression was strongly associated with reduced cytolytic activity scores, suggesting suppressed antitumor immunity. In the MDACC HGSOC cohort (NCT03026062), patients with elevated METTL5 expression in baseline tumor samples exhibited significantly poorer responses and shorter overall survival after ICB therapy, supporting its clinical relevance. Mechanistically, METTL5 loss in OC models specifically reduced m6A methylation at A1832 of 18S rRNA, disrupting helix 44 structure and impairing ribosomal scanning and translation. RiboLace-based active ribosome profiling demonstrated that METTL5 knockout reprograms translation, notably downregulating genes enriched in the “Response of EIF2AK1 to Heme Deficiency” pathway, consistent with defective integrated stress response (ISR). Translation of ATF4 was markedly reduced, accompanied by decreased expression of downstream targets SLC7A11 and SLC3A2, key components of the cystine/glutamate antiporter that suppress lipid peroxidation and ferroptosis. As a result, METTL5-deficient OC cells displayed increased lipid peroxidation and heightened sensitivity to T cell-mediated ferroptosis in vitro and in vivo. Reintroduction of ATF4 restored SLC7A11/SLC3A2 expression and reversed ferroptosis sensitivity, while pharmacologic inhibition of ferroptosis produced similar effects. These findings identify METTL5 as a central regulator of ATF4 translation, oxidative stress control, and immune resistance in OC. Elevated METTL5 expression may serve as a biomarker for poor ICB response. Therapeutically, METTL5 inhibition, ATF4 translation suppression or ferroptosis induction represent potential strategies to enhance immunotherapy efficacy. This study establishes the METTL5-ATF4-ferroptosis axis as a critical tumor-intrinsic mechanism of immune evasion and provides a generalizable framework for decoding cancer-immune interactions. Citation Format: Jiakai Hou, Cheng-wei Ju, Nicholas A. Egan, Yanjun Wei, Yunfei Wang, Minghao Dang, Tianyi Zhou, Leilei Shi, Ningbo Zheng, Si Chen, Ashley Guerrero, Xiaofang Liang, Wanfu Wu, Areej Akhtar, Chitra Dhiman, Debanwita Roy Burman, Andro Gerges, Mason D. Flores, Han Li, Li-Sheng Zhang, Marleen Kok, Xiaobo Mao, Linghua Wang, Qin Feng, Yiwen Chen, Sanghoon Lee, Daniel McGrail, Nidhi Sahni, Chuan He, Amir A. Jazaeri, Weiyi Peng. Tumor-intrinsic METTL5 restricts T cell-induced ferroptosis by impairing ATF4 translation in ovarian cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2915.
Hou et al. (2026) studied this question.