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).
Authors
- Haiyan Hu (ORCID: https://orcid.org/0000-0002-3993-974X)
- Qiang Gao (ORCID: https://orcid.org/0000-0002-6695-9906)
- Xupeng Yang (ORCID: https://orcid.org/0009-0005-7624-6722)
- Wenxin Qin (ORCID: https://orcid.org/0000-0002-1989-3027)
- Wanguang Zhang (ORCID: https://orcid.org/0000-0003-3184-9907)
- Qunlun Shen (ORCID: https://orcid.org/0000-0002-7149-6803)
- Hao Feng (ORCID: https://orcid.org/0000-0003-4066-8104)
- Shuyi Ji (ORCID: https://orcid.org/0009-0002-5348-1234)
- Jinghan Zhu (ORCID: https://orcid.org/0000-0002-6310-1672)
- Xifu Cheng (ORCID: https://orcid.org/0009-0009-6262-308X)
- Haigang Geng (ORCID: https://orcid.org/0009-0002-9658-4444)
- Chen Guang Yang (ORCID: https://orcid.org/0000-0002-1237-2632)
- Jing‐Ping Yun (ORCID: https://orcid.org/0000-0002-1001-0769)
- Zhicheng Liu (ORCID: https://orcid.org/0000-0002-5950-409X)
- Lingyi Fu (ORCID: https://orcid.org/0000-0002-3519-3127)
- Maolan Li (ORCID: https://orcid.org/0000-0002-5183-9418)
- Youpei Lin (ORCID: https://orcid.org/0000-0002-2914-2075)
- Xin Chen (ORCID: https://orcid.org/0000-0003-3885-4944)
- Cun Wang (ORCID: https://orcid.org/0000-0002-4977-2189)
- Quan Zheng (ORCID: https://orcid.org/0000-0002-4512-9233)
- Xia Yang (ORCID: https://orcid.org/0000-0002-4322-865X)
- Yansong Lin (ORCID: https://orcid.org/0000-0002-4977-0052)
- Xuhui Ma (ORCID: https://orcid.org/0009-0000-3833-4055)
- Chao Leng
- Xiujiao Shen
- Yuhan Xia
- Nuo Xu
- Rongce Zhao
- Haoyu Zhang
- Qian Li (ORCID: https://orcid.org/0009-0008-9946-5137)
- Shuo Li (ORCID: https://orcid.org/0009-0002-0884-6599)
- Yan Li (ORCID: https://orcid.org/0009-0002-8963-8889)
- Zihan Chen (ORCID: https://orcid.org/0009-0008-8567-9230)
Institutions
- Sun Yat-sen University (CN)
- Shanghai Jiao Tong University (CN)
- Peking University (CN)
- Fudan University (CN)
- Renji Hospital (CN)
- Jinshan Hospital of Fudan University (CN)
- Shanghai Cancer Institute (CN)
- Zhongshan Hospital (CN)
- Shanghai Sixth People's Hospital (CN)
- Sun Yat-sen University Cancer Center (CN)
- Tongji Hospital (CN)
- State Key Laboratory of Oncology in South China (CN)
- Huazhong University of Science and Technology (CN)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-11-11
- DOI
- https://doi.org/10.1158/2159-8290.cd-26-0498
- Primary Topic
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00