Spatiotemporal mapping of tertiary lymphoid structure heterogeneity shapes immune niches and clinical outcomes in intrahepatic cholangiocarcinoma.

Authors

Liaoliao Gao, Jie Mei, Libing Hong, Yuzhi Jin, Jinlin Cheng, Xuqi Sun, Chuan Liu, Bin Li, Xiaomeng Dai, Bo Lin, Yajie Sun, Peng Zhao, Minshan Chen, Rongping Guo, Shan Xin, Jingping Yun, Inmaculada Martínez-Reyes, Wei Wei, Weijia Fang, Xuanwen Bao

Published in

Science advances. Volume 12. Issue 37. Pages eaeb7225. Sep 11, 2026. Epub Sep 09, 2026.

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal malignancy with limited therapeutic options. The spatial architecture and functional diversity of tertiary lymphoid structures (TLSs) in iCCA remain unclear. Here, we present a multimodal spatial atlas of TLSs and identified intratumoral TLSs (iTLSs) as independent prognostic markers. Bulk proteomic profiling of 214 discovery and 155 validation cases identified a four-tier TLS-based tumor microenvironment classification system and supported development of a TLS-predictive random forest classifier. Imaging mass cytometry revealed that iTLS⁺ tumors harbor structured immune architectures, where M1-like tissue-resident macrophages (RTMs), dendritic cells, and CXCL13⁺ CD4⁺ T cells colocalize to form antigen-presenting neighborhoods (apc-CNs) spatially coupled to TLS core regions (TLScore-CNs). Single-cell spatial transcriptomics further resolved 61 TLSs into 14 spatial niches and defined a pseudotemporal maturation continuum: aggregated, activated, and postactivated. Intraniche communication, primarily mediated by ifnCAFs, iCAFs, and CXCL12⁺ macrophages, evolved dynamically with maturation. Single-nucleus RNA sequencing combined with Tangram-based spatial mapping revealed CXCL12⁺ macrophages and iCAFs forming a peripheral band in aggregated TLSs, whereas ifnCAFs infiltrated TLS interiors during activation. These findings define TLS heterogeneity and provide insights for stroma-directed immunotherapy.

PMID:
42715308
Bibliographic data and abstract were imported from PubMed on 10 Sep 2026.

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