Latent Squamous Plasticity Licensed by Chromatin-State Remodeling Dictates Therapeutic Susceptibility in Cholangiocarcinoma

Adenosquamous carcinoma (ASC) in intrahepatic cholangiocarcinoma (iCCA) has long been considered rare (~1-2%), yet its occurrence portends lethal disease progression. Here, we identify latent squamous plasticity, a transcriptionally primed yet histology-silent state that is quantifiable by a squamous transition potential (STP) index. Approximately 20-30% of iCCA patients can be classified as STP-high and experience ASC-like dismal outcomes. Mechanistically, FOSL1 acts as a plasticity trigger, driving a temporally ordered squamous program by reshaping the chromatin landscape. Additionally, it cooperates with p63 in an enhancer-dependent manner to dysregulate PTGS2/COX-2 expression. The resulting intratumoral PGE2 accumulation drives neutrophil-mediated FOXP3-negative type 1 regulatory T-cell (Tr1) polarization and predisposes STP-high tumors to immunotherapy resistance. Through a drug-repurposing screen, we identify celecoxib as a dual-function agent that counteracts latent squamous plasticity while fostering an immune-permissive state, providing a clinically actionable strategy for squamous-biased iCCA now being evaluated in a phase Ib/II trial (NCT07632235).