Targeting PI3Kδ suppresses pancreatic cancer by dual disruption of fibrosis and immune evasion.

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.