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Adv."],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:p>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    tumors harbor structured immune architectures, where M1-like tissue-resident macrophages (RTMs), dendritic cells, and CXCL13\n                    <jats:sup>+<\/jats:sup>\n                    CD4\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    macrophages, evolved dynamically with maturation. Single-nucleus RNA sequencing combined with Tangram-based spatial mapping revealed CXCL12\n                    <jats:sup>+<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeb7225","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T17:58:47Z","timestamp":1788976727000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Spatiotemporal mapping of tertiary lymphoid structure heterogeneity shapes immune niches and clinical outcomes in intrahepatic cholangiocarcinoma"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4227-5889","authenticated-orcid":true,"given":"Liaoliao","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5676-4216","authenticated-orcid":true,"given":"Jie","family":"Mei","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China."},{"name":"State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6049-7206","authenticated-orcid":true,"given":"Libing","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7462-8058","authenticated-orcid":true,"given":"Yuzhi","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlin","family":"Cheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3975-9917","authenticated-orcid":true,"given":"Xuqi","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5324-3554","authenticated-orcid":true,"given":"Bin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0673-1886","authenticated-orcid":true,"given":"Xiaomeng","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China."},{"name":"National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5682-2140","authenticated-orcid":true,"given":"Bo","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Software, Zhejiang University, Ningbo, China."},{"name":"Innovation Centre for Information, Binjiang Institute of Zhejiang University, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4611-230X","authenticated-orcid":true,"given":"Yajie","family":"Sun","sequence":"additional","affiliation":[{"name":"Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5479-899X","authenticated-orcid":true,"given":"Peng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China."},{"name":"National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minshan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China."},{"name":"State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongping","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China."},{"name":"State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong 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