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Targeting the DNA damage response (DDR) with kinase inhibitors may enhance tumor susceptibility to radiotherapy (RT). While RT is known to alter the immune phenotype of HNSCC cells, its impact on innate immune responses, particularly on natural killer (NK) cells, remains unclear. We therefore investigated how RT combined with ATM or ATR inhibition\u2014key DDR kinases\u2014affects NK cell-mediated killing and activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The tumor cell lines HSC4 and Cal33 (both HPV-negative) and UM-SCC-47 and UD-SCC\u20112 (both HPV-positive) were treated with the DDR inhibitors VE-822 (ATRi) and AZD0156 (ATMi) and hypofractionated RT (2\u202f\u00d7\u20095\u202fGy). After co-cultivation with primary human NK cells, tumor cell death was measured using flow cytometry after 24\u202fh. Further, NK cell activation markers and the supernatant of tumor cell\u2013NK cell co-cultures were measured and the effect of immune checkpoint inhibitors (durvalumab, monalizumab) was additionally investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Particularly the HPV-negative HSC4 cells pretreated with either ATMi or RT\u202f+\u2009ATMi showed significantly increased killing by NK cells. Reduced secretion of granulysin by NK cells was mainly found in the co-cultures of HPV-negative HNSCC treated with ATRi. Treatment with the immune checkpoint inhibitor durvalumab (anti-PD-L1) did not result in significant augmentation of NK cell-induced tumor cell killing in this setting. Conversely, treatment with monalizumab (anti-NKG2A) resulted in a\u00a0modest increase.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Natural killer cells showed only a\u00a0limited contribution to the killing of HNSCC cells pretreated with RT or RT\u202f+\u2009DDRi. However, a\u00a0subset of patients with head and neck tumors\u2014such as those represented by the HSC4 model\u2014might still benefit from combining RT with ATMi rather than ATRi to enhance NK cell-mediated tumor killing.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00066-026-02522-3","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T08:48:31Z","timestamp":1776415711000},"page":"1071-1082","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Radiotherapy and DNA damage response inhibitors modestly sensitize HNSCC to NK cell killing, with ATM inhibition more effective than ATR inhibition"],"prefix":"10.1007","volume":"202","author":[{"given":"Leonie","family":"Steinsd\u00f6rfer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilli","family":"Z\u00fclch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Sch\u00e4fer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Frey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Corradini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer","family":"Fietkau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Udo S.","family":"Gaipl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8767-3774","authenticated-orcid":false,"given":"Tina","family":"Jost","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"2522_CR1","doi-asserted-by":"publisher","unstructured":"Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR, Head and neck squamous cell carcinoma. 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All results presented in this manuscript are covered by the ethical approval of the IMMO-NHD trial, and written informed consent was obtained from all donors. Approval was granted by the institutional review board of Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg on November\u00a09, 2022 (application number 21-415-B). Blood cells were isolated from leukoreduction system chambers (LRSC) of healthy, anonymous donors having undergone a\u00a0strict health check by the Transfusion Medicine and Hemostaseology Department of the Universit\u00e4tsklinikum Erlangen (Germany). The permission to use this LRSC was given by the institutional review board at Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg approved the study (no. 48_19 B; approved September\u00a012, 2019). The study was performed in accordance with the Declaration of Helsinki. All patients gave written informed consent that comprised a\u00a0data privacy clause for data collection and analysis for research purposes.","order":2,"name":"Ethics","label":"Ethical standards","group":{"name":"EthicsHeading","label":"Declarations"}}]}}