Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense stromal fibrosis that promotes immune exclusion and treatment resistance, yet the upstream drivers of this pro-fibrotic cascade remain poorly defined. Here, we identify phosphoinositide 3-kinase δ (PI3Kδ) as a previously unrecognized driver of fibrosis in PDAC. Pharmacological inhibition of PI3Kδ reduces collagen deposition while enhancing the infiltration of activated CD8+ T cells, thereby reprogramming the tumor microenvironment toward an antitumor state. Mechanistically, we reveal that PI3Kδ regulates the biosynthesis of lysophosphatidic acid (LPA), a key lipid mediator of stromal remodeling, by controlling phosphatidylcholine-derived precursors in both cancer cells and stromal fibroblasts. By regulating both LPA-driven stromal remodeling and immune suppression, PI3Kδ emerges as a central regulator of the PDAC tumor microenvironment. Co-inhibition of autotaxin, an enzyme contributing to LPA production, and PI3Kδ further amplifies stromal disruption and improves chemo-immunotherapy efficacy in preclinical PDAC models. These findings position PI3Kδ as a central therapeutic target in PDAC, offering a dual-action strategy to simultaneously dismantle stromal fibrosis and immune suppression.
Garczyk et al. (Mon,) studied this question.