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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.<\/jats:p>","DOI":"10.1084\/jem.20250272","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T02:20:49Z","timestamp":1747794049000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["YTHDFs as radiotherapy checkpoints in tumor immunity"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4416-116X","authenticated-orcid":true,"given":"Chuangyu","family":"Wen","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/024mw5h28","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Chicago 1 Department of Radiation and Cellular Oncology, , Chicago, IL,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/024mw5h28","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Center for Metastasis Research, University of Chicago 2 , Chicago, IL,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5445-9313","authenticated-orcid":true,"given":"Emile Z.","family":"Naccasha","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/024mw5h28","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Chicago 1 Department of Radiation and Cellular Oncology, , Chicago, IL,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/024mw5h28","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Center for Metastasis Research, University of Chicago 2 , Chicago, IL,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4319-7424","authenticated-orcid":true,"given":"Chuan","family":"He","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/024mw5h28","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Biophysical Dynamics, University of Chicago 3 Department of Chemistry, Department of Biochemistry and Molecular Biology, , Chicago, IL,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/024mw5h28","id-type":"ROR","asserted-by":"publisher"}],"name":"Howard Hughes Medical Institute, University of Chicago 4 , Chicago, IL,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5512-8595","authenticated-orcid":true,"given":"Hua Laura","family":"Liang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/024mw5h28","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Chicago 1 Department of Radiation and Cellular Oncology, , Chicago, IL,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/024mw5h28","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Center for Metastasis Research, University of Chicago 2 , Chicago, IL,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5643-8939","authenticated-orcid":true,"given":"Ralph R.","family":"Weichselbaum","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/024mw5h28","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Chicago 1 Department of Radiation and Cellular Oncology, , Chicago, IL,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/024mw5h28","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Center for Metastasis Research, University of Chicago 2 , Chicago, IL,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2025,6,5]]},"reference":[{"key":"2025060509255414500_bib1","doi-asserted-by":"publisher","first-page":"1919","DOI":"10.1056\/NEJMoa1709937","article-title":"Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer","volume":"377","author":"Antonia","year":"2017","journal-title":"N. 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