{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T05:55:00Z","timestamp":1781848500258,"version":"3.54.5"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Poly (ADP-ribose) polymerase inhibitors (PARPi) have improved outcomes in ovarian cancer with homologous recombination deficiency (HRD). However, approximately half of high-grade serous ovarian cancers retain intact homologous recombination repair and are classified as homologous recombination\u2013proficient (HRP), limiting the clinical benefit of PARPi in this population. Strategies capable of pharmacologically inducing a functional HRD-like state may expand the therapeutic scope of PARPi.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A drug repurposing screen of 97 FDA-approved targeted agents was conducted in olaparib-insensitive HRP ovarian cancer cell models. Drug interactions were evaluated using cell viability and colony formation assays. Homologous recombination activity was assessed using RAD51 foci formation and DR-GFP reporter assays. DNA damage, cell cycle distribution, and apoptosis were analysed using immunofluorescence and flow cytometry. Antitumour efficacy was evaluated in xenograft models. Immune recognition-related features and susceptibility to CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell-mediated killing\n                      <jats:italic>in vitro<\/jats:italic>\n                      were assessed using peripheral blood mononuclear cell (PBMC) coculture assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Proteasome inhibitors emerged as the most consistent sensitising drug class. The oral proteasome inhibitor ixazomib citrate demonstrated robust synergy with olaparib across multiple HRP ovarian cancer models. Mechanistically, ixazomib citrate disrupted recruitment of the homologous recombination protein RAD51 to DNA damage sites without reducing its expression, thereby inducing a functional HRD-like state consistent with BRCAness. This disruption increased olaparib-induced DNA damage, resulting in G2\/M arrest and apoptosis. In xenograft models, combination therapy significantly suppressed tumour growth compared with either agent alone. Proteasome inhibition also increased tumour-surface MHC class I expression and appeared to enhance susceptibility to CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell-mediated tumour cell killing\n                      <jats:italic>in vitro<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Ixazomib citrate sensitised HRP ovarian cancer models to PARP inhibition by functionally impairing homologous recombination repair. These findings provide preclinical support for proteasome inhibition as a PARPi-sensitising strategy in HRP ovarian cancer. The immune-related observations are based primarily on\n                      <jats:italic>in vitro<\/jats:italic>\n                      coculture experiments and should therefore be considered exploratory. Further validation in additional preclinical and clinically relevant models is warranted.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1828316","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T05:48:30Z","timestamp":1781848110000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Proteasome inhibition induces a BRCAness-like state and sensitises HR-proficient ovarian cancer models to PARP inhibitors"],"prefix":"10.3389","volume":"17","author":[{"given":"Ruiju","family":"He","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]},{"name":"Shanghai Key Laboratory of Gynaecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingting","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]},{"name":"Shanghai Key Laboratory of Gynaecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]},{"name":"Shanghai Key Laboratory of Gynaecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, 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China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyan","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]},{"name":"Shanghai Key Laboratory of Gynaecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anyue","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]},{"name":"Shanghai Key Laboratory of Gynaecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, 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