Robatel, SteveSteveRobatelHillen, HanneHanneHillenMutisheva, IvaninaIvaninaMutishevaMüller, Joshua C.Joshua C.MüllerWartenberg, MartinMartinWartenberg0000-0002-5378-3825Ma, FeiyangFeiyangMaBäriswyl, LukasLukasBäriswylEvenepoel, JefJefEvenepoelScheele, Colinda L. G. J.Colinda L. G. J.ScheeleLee, Delphine J.Delphine J.LeeModlin, Robert L.Robert L.ModlinKessler, UlfUlfKesslerNobis, MaxMaxNobisZ'graggen, KasparKasparZ'graggenSchenk, MirjamMirjamSchenk0000-0002-1637-07302026-02-032026-02-032026-02-01https://boris-portal.unibe.ch/handle/20.500.12422/230937Background Despite advances, immunotherapy has shown limited efficacy in pancreatic ductal adenocarcinoma (PDAC). The profoundly immunosuppressive tumor microenvironment (TME) of PDAC restricts effective antitumor immune responses, necessitating the development of novel therapeutic approaches. Emerging evidence suggests that modulating the TME could enhance immunotherapy outcomes, with glucocorticoid-induced TNFR-related protein (GITR) presenting as a promising target.Methods We performed in vivo studies using the Pan02 mouse model of PDAC, where we activated GITR. Complementary analyses were performed on human PDAC samples that were obtained from surgical resections, both from treatment-naive patients and those undergoing neoadjuvant chemotherapy. Human PDAC samples were assessed using scRNA-seq, spatial transcriptomics, and immunofluorescence.Results GITR was found to be significantly overexpressed in PDAC tissues compared to normal adjacent pancreatic tissue, with further upregulation observed following neoadjuvant chemotherapy. These findings were corroborated in Pan02 mouse model. GITR activation in vivo led to a reduction in regulatory T cells (Tregs) and an increase in activated cytotoxic effector cells within the TME, resulting in suppressed tumor growth and extended survival. Spatial transcriptomic analysis revealed that GITR expression was predominantly localized to lymphocytes in close proximity to tumor cells in human PDAC. Additionally, long-term survival PDAC patients showed high levels of GITR+ lymphocytes, underscoring its clinical relevance.Conclusions This study identifies GITR as a key regulator of the immunosuppressive TME in PDAC. By promoting T cell activation and effector functions, GITR represents a promising target for immunotherapeutic treatment in PDAC. Combining GITR activation with standard chemotherapy may offer a promising strategy to improve outcomes for PDAC patients.enImmunomodulationImmunotherapyPancreatic ductal adenocarcinomaTranscriptomicsTumor microenvironmentarticle10.48620/943044162098310.1007/s00535-026-02347-y