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Review
. 2025 Aug 4;222(8):e20250272.
doi: 10.1084/jem.20250272. Epub 2025 Jun 5.

YTHDFs as radiotherapy checkpoints in tumor immunity

Chuangyu Wen  1   2 , Emile Z Naccasha  1   2 , Chuan He  3   4 , Hua Laura Liang  1   2 , Ralph R Weichselbaum  1   2
Affiliations
Review

YTHDFs as radiotherapy checkpoints in tumor immunity

Chuangyu Wen et al. J Exp Med. .

Abstract

Radiotherapy (RT), a cornerstone of cancer treatment, exerts its therapeutic effects primarily by inducing DNA damage in tumor cells and modulating the tumor immune microenvironment (TIME). Despite its efficacy, RT is often counteracted by tumor-intrinsic mechanisms, such as DNA damage repair, as well as immune-suppressive responses. YTHDF proteins, key N6-methyladenosine (m6A) readers, have emerged as pivotal regulators of tumor progression, DNA repair, and immune cell function, making them promising targets for enhancing RT efficacy. In this review, we explore the dual roles of YTHDF proteins in modulating both tumor-intrinsic and immune-mediated responses to RT. We summarize their influence on DNA damage repair pathways in tumor cells and their impact on the TIME, which collectively shape the antitumor efficacy of RT. Furthermore, we discuss recent advances in the development of YTHDF-targeting inhibitors and their potential to synergize with RT and immunotherapy, offering new avenues to improve cancer treatment outcomes.

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Conflict of interest statement

Disclosures: C. He reported serving as a scientific co-founder and as a member of the scientific advisory board for Aferna Green, Inc., AllyRNA Inc, and Ellis Bio, Inc. Additionally, C. He holds equity in Aferna Green, Inc., Ellis Bio, Inc., AllyRNA, Inc., and Accent Therapeutics, Inc. R.R. Weichselbaum has stock and other ownership interests with Boost Therapeutics, Immvira LLC, Reflexion Pharmaceuticals, Coordination Pharmaceuticals Inc., Magi Therapeutics, Oncosenescence, Aqualung Therapeutics Corporation, Cyntegron, Fuse Oncology, and PersonaDX. He has served in a consulting or advisory role for Aettis Inc., AstraZeneca, Coordination Pharmaceuticals, Genus, Merck Serono S.A., Nano Proteagen, NKGen Biotech, Shuttle Pharmaceuticals, Highlight Therapeutics, S.L., Aqualung Therapeutics Corporation. In addition, R.R. Weichselbaum has received industry research grants from Varian and Regeneron, and holds patents on metastasis signatures and cGAS-STING IR. No other disclosures were reported.

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