Abstract A030: IRF1-dependent plasticity shapes niche-specific pancreatic cancer cell fitness and immune context

Abstract

Pancreatic ductal adenocarcinoma (PDA) contains spatially distinct microenvironments that support transcriptionally diverse tumor cell states. Yet how transcriptional plasticity enables adaptation to these niches while shaping local host responses remains incompletely understood. Here, we identify Interferon Regulatory Factor 1 (IRF1) as a context-dependent regulator of PDA cell plasticity that links tumor cell fitness to microenvironmental conditions. Pooled CRISPR-Cas9 screening revealed IRF1 as a selective dependency for PDA cell fitness in vivo. In human PDA specimens, IRF1 was not recurrently mutated but was expressed in spatially restricted tumor cell subsets. Under interferon gamma inflammatory conditions, IRF1 promoted PDA cell survival and was required from MHC-I expression, linking IRF1 activity to an antigen presentation program associated with a CD8+ T cell-infiltrated niche. In parallel, in vivo competition assays and in vitro deprivation studies uncovered an immune-independent role for IRF1 in supporting PDA cell fitness under competitive and serum-limited conditions. Quantitative spatial analyses of human PDA further showed IRF1-positive and IRF1-negative tumor cells to be spatially segregated and show distinct cellular neighbors. Together, these findings identify IRF1-dependent transcriptional plasticity as a mechanism through which tumor cells navigate evolutionary tradeoffs between niche-specific fitness and immune visibility. AI was used to produce new text in this abstract and all authors reviewed the completed abstract to very the accuracy and integrity of all statements prior to submission.