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ATR is a key mediator of the replication stress response and plays a vital role in maintaining genomic stability. This study investigates the immunomodulatory potential of the ATR inhibitor (ATRi) tuvusertib to improve the targeting of prostate cancer (PCa) by immunotherapy. Tuvusertib pretreatment sensitized human PCa cells (DU145 and 22Rv1) to PBMC-derived natural killer (NK)-mediated lysis. Flow cytometric analysis identified upregulation of death receptor tumor-necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), NKG2D ligand ULBP-1, and programmed death-ligand 1 (PD-L1) as a potential immunomodulatory effect of tuvusertib. Enhanced avelumab-mediated antibody-dependent cell-mediated cytotoxicity and lysis by PD-L1 targeting high-affinity NK (PD-L1 t-haNK) cells were observed in tuvusertib-treated DU145. Tuvusertib sensitized cells to lysis by recombinant human TRAIL, and TRAIL signaling blockade reduced NK-mediated lysis of tuvusertib-exposed cells. RNA analysis revealed elevated p21 and reduced Bcl-xL transcript levels in tuvusertib-treated DU145, suggesting an accumulation of DNA damage and suppression of anti-apoptotic signaling, respectively. Pretreatment of NK cells with the interleukin-15 (IL-15) receptor superagonist N-803 (nogapendekin alfa inbakicept) further enhaced the lysis of tuvusertib-exposed cells. In vivo in the DU145 PCa xenograft model, tuvusertib and N-803 combination therapy demonstrated marked and significant antitumor efficacy relative to either monotherapy, eliciting superior tumor growth control and prolonging survival. Our findings support further investigation into the use of ATRi with immune checkpoint blockade and\/or immune-stimulating agents in prostate cancer.<\/jats:p>","DOI":"10.1007\/s00262-025-04260-4","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T06:22:45Z","timestamp":1766125365000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The ATR inhibitor tuvusertib (M1774) sensitizes prostate carcinoma to natural killer cell-mediated cytotoxicity, which is further augmented by the IL-15 receptor superagonist N-803"],"prefix":"10.1007","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5188-151X","authenticated-orcid":false,"given":"Cailyn A.","family":"Lee","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7932-4072","authenticated-orcid":false,"given":"Jeffrey","family":"Schlom","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5282-3154","authenticated-orcid":false,"given":"James W.","family":"Hodge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0273-5647","authenticated-orcid":false,"given":"Kellsye P.","family":"Fabian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"4260_CR1","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1016\/S0140-6736(21)00950-8","volume":"398","author":"S Sandhu","year":"2021","unstructured":"Sandhu S, Moore CM, Chiong E, Beltran H, Bristow RG, Williams SG (2021) Prostate cancer. 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