Klein, LukasTu, MengyuKrebs, NiklasUrbach, LauraGrimm, DanielaLatif, Muhammad UmairPenz, FrederikeBlandau, AnnaWu, XueyanSamuel, Rebecca DiyaKüffer, StefanWegwitz, FlorianChan, NathanAliar, KazeeraVyas, ForamKishore, UdayHessmann, ElisabethTrumpp, AndreasEspinet, ElisaPapantonis, ArgyrisKhokha, RamaEllenrieder, VolkerGrünwald, Barbara T.Singh, Shiv K.2025-04-152025-04-152025-12-012041-1723https://hdl.handle.net/2445/220472Pancreatic 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 regulation is amplified via regional TNF-α+ macrophages, which associates with a reactive phenotype and reduced CD8+ T cell infiltration in patients. Consequently, combined preclinical anti-TNF-α immunotherapy and chemotherapy reduces macrophages and promotes CD3+/CD8+ T cell infiltration in basal-like PDAC, improving survival. Hence, tumor cell-intrinsic epigenetic programs, together with extrinsic microenvironmental cues, facilitate intratumoral subtype heterogeneity and disease progression.19 p.application/pdfengcc-by (c) Klein, L. et al., 2025http://creativecommons.org/licenses/by/4.0/Càncer de pàncreesTumorsLimfòcitsEpigènesiPancreas cancerTumorsLymphocytesEpigenesisinfo:eu-repo/semantics/article2025-04-15info:eu-repo/semantics/openAccess39762215