biostudies-literatureKlein LDeutsche ForschungsgemeinschaftWilhelm Sander-StiftungDeutsche Forschungsgemeinschaft (German Research Foundation)Wilhelm Sander-Stiftung (Wilhelm Sander Foundation)Fritz Thyssen StiftungDeutsche KrebshilfeFritz Thyssen Stiftung (Fritz Thyssen Foundation)Deutsche Krebshilfe (German Cancer Aid)335https://www.ebi.ac.uk/biostudies/studies/S-EPMC11704331biostudies-literatureUnknown16(1)Pancreatic ductal adenocarcinoma (PDAC) displays a high degree of spatial subtype heterogeneity and co-existence, linked to a diverse microenvironment and worse clinical outcome. However, the underlying mechanisms remain unclear. Here, by combining preclinical models, multi-center clinical, transcriptomic, proteomic, and patient bioimaging data, we identify an interplay between neoplastic intrinsic AP1 transcription factor dichotomy and extrinsic macrophages driving subtype co-existence and an immunosuppressive microenvironment. ATAC-, ChIP-, and RNA-seq analyses reveal that JUNB/AP1- and HDAC-mediated epigenetic programs repress pro-inflammatory signatures in tumor cells, antagonizing cJUN/AP1 signaling, favoring a therapy-responsive classical neoplastic state. This dichotomous regulationNature communicationsSpatial tumor immune heterogeneity facilitates subtype co-existence and therapy response in pancreatic cancer.PMC1170433170112999701150542021.159.1 and 2021.159.2KFO500210.20.2.038MN; 10.23.2.021MNPenz FKrebs NSamuel RDBlandau AKuffer SEspinet EUrbach LTu MKlein LPapantonis AVyas FAliar KHessmann ELatif MUTrumpp AGrunwald BTKishore UKhokha REllenrieder VChan NWegwitz FGrimm DWu XSingh SKfalseSpatial tumor immune heterogeneity facilitates subtype co-existence and therapy response in pancreatic cancer.Pancreatic ductal adenocarcinoma (PDAC) displays a high degree of spatial subtype heterogeneity and co-existence, linked to a diverse microenvironment and worse clinical outcome. However, the underlying mechanisms remain unclear. Here, by combining preclinical models, multi-center clinical, transcriptomic, proteomic, and patient bioimaging data, we identify an interplay between neoplastic intrinsic AP1 transcription factor dichotomy and extrinsic macrophages driving subtype co-existence and an immunosuppressive microenvironment. ATAC-, ChIP-, and RNA-seq analyses reveal that JUNB/AP1- and HDAC-mediated epigenetic programs repress pro-inflammatory signatures in tumor cells, antagonizing cJUN/AP1 signaling, favoring a therapy-responsive classical neoplastic state. This dichotomous regulation2025-01-01T00:00:00Z2025 Jan2026-06-01T15:01:02.491Z2026-04-08T13:34:33.297ZS-EPMC117043313976221510.1038/s41467-024-55330-7