Authors
Niccolò Bragato, Ana Beatriz Dias, Anna Ohradanova-Repic, Alma Dupanovic, Filip Horvat, Patrick Fischer, Lisa-Marie Appel, Lena Walch, Ava Kleinwächter, Anna Röhrer, Sylvia Kerschbaum-Gruber, Sandra Barna, Piero Fossati, Dietmar Georg, Joachim Widder, Klaus Podar, Michael Cohen, Dea Slade
Published in
Molecular therapy. Oncology. Volume 34. Issue 3. Pages 201258. Sep 17, 2026. Epub Jun 08, 2026.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of pancreatic cancer with a poor prognosis and resistance to conventional radio- and chemotherapy. Radiation can induce pro-inflammatory signaling by activating the type 1 interferon (IFN-I) response, which can be enhanced by targeting negative regulators of the IFN-I pathway, such as ADP-ribosyltransferase PARP7. Here, we show that PARP7 inhibitors (PARP7i) enhance radiation-induced cell death and promote STING- and NF-κB-dependent immunogenic signaling in PDAC cells, leading to inflammatory gene expression and cytokine release. These effects were most pronounced in BxPC-3 cells, which exhibit higher baseline expression of PARP7, AHR, and interferon response genes. PARP7i potentiated the immunogenic effects of hypofractionated radiation by inducing a STING-dependent IFN-I response, leading to immunogenic cell death and activation of monocytes and NK cells. Carbon ion irradiation elicited stronger immunogenicity than X-rays when combined with PARP7i. KRAS-mutated PANC-1 cells showed a higher expression of enzymes that convert ATP to immunosuppressive adenosine, which was enhanced by radiation. This may explain why PARP7i were more effective as monotherapy in PANC-1 cells, promoting NK cell activation. These findings support further evaluation of PARP7i in PDAC in combination with radiotherapy or as monotherapy, depending on the immunosuppressive effects of radiation.
PMID:
42383254
Bibliographic data and abstract were imported from PubMed on 01 Jul 2026.
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