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Tertiary lymphoid structures (TLSs) are critical modulators of antitumor immunity; however, the immunological dynamics, particularly the roles of B cells and their interactions with naive T cells in PSCC tissues, remain inadequately understood. This study integrates transcriptomic approaches, including spatial transcriptomics, single\u2010cell sequencing (scRNA\u2010seq), and bulk RNA sequencing (bulk RNA\u2010seq), and immunohistochemistry to elucidate the immune architecture of and functional mechanisms within TLSs. The results reveal a positive correlation between TLS density and patient survival, with CD74\u207a B cells tending to be enriched during early TLS formation. These cells exhibit strong immune activation and a propensity to differentiate into plasma cells. By engaging with naive T cells through\n                    <jats:italic>HLA\u2010DRA<\/jats:italic>\n                    via ligand\u2013receptor interactions, CD74\u207a B cells activate transcription factors, including\n                    <jats:italic>NFKB1<\/jats:italic>\n                    ,\n                    <jats:italic>NFKB2<\/jats:italic>\n                    ,\n                    <jats:italic>NFATC1<\/jats:italic>\n                    ,\n                    <jats:italic>NFATC2<\/jats:italic>\n                    ,\n                    <jats:italic>FOS<\/jats:italic>\n                    , and\n                    <jats:italic>RUNX1<\/jats:italic>\n                    , in naive T cells, thereby enhancing the immune response. Consequently, CD74\u207a B cells represent a compelling biomarker for and therapeutic target of PSCC, offering profound insights into the immunological mechanisms that drive PSCC progression and response to immunotherapy.\n                  <\/jats:p>","DOI":"10.1002\/advs.202509742","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T14:52:12Z","timestamp":1760971932000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Spatial Transcriptional Dynamics of CD74\u207a B Cells in Tertiary Lymphoid Structures Drive Immune Evolution in Penile Squamous Cell Carcinoma"],"prefix":"10.1002","volume":"12","author":[{"given":"Ting","family":"Xue","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010sen University Cancer Center  Guangzhou 510060 China"},{"name":"Department of Urology Sun Yat sen University Cancer Center  Guangzhou 510060 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuangzhong","family":"Deng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010sen University Cancer Center  Guangzhou 510060 China"},{"name":"Department of Musculoskeletal Oncology Sun Yat\u2010sen University Cancer Center  Guangzhou 510060 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingya","family":"Liu","sequence":"additional","affiliation":[{"name":"BioMega Spatiotemporal Pathology Research Center  Zhuhai 519000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Oncology Guizhou Provincial People's Hospital  Guizhou 550008 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology Cancer Hospital Affiliated to Guangzhou Medical University  Guangzhou 510030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiheng","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Urology Xiangya Hospital Central South University  Changsha 410008 China"},{"name":"Department of Dermatology Xiangya Hospital Central South University  Changsha 410008 China"},{"name":"National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology  Changsha 410008 China"},{"name":"Furong Laboratory  Changsha 410008 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueying","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology The Seventh Affiliated Hospital Sun Yat\u2010sen University  Shenzhen 518107 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Pathology Sun Yat\u2010sen University Cancer Center  Guangzhou 510060 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jietian","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Pathology Sun Yat\u2010sen University Cancer Center  Guangzhou 510060 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongzhen","family":"Tang","sequence":"additional","affiliation":[{"name":"BioMega Spatiotemporal Pathology Research Center  Zhuhai 519000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Urology Shenzhen People's Hospital The Second Clinic Medical College of Jinan University  Shenzhen 518020 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Zuo","sequence":"additional","affiliation":[{"name":"Clinical Medicine Guangzhou University of Chinese Medicine  Guangzhou 510060 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Liang","sequence":"additional","affiliation":[{"name":"Shenzhen Kangning Hospital  Shenzhen 518020 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongbin","family":"Wang","sequence":"additional","affiliation":[{"name":"Dongguan Key Laboratory of Public Health Laboratory Science School of Public Health Guangdong Medical University  Dongguan 523808 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2430-7934","authenticated-orcid":false,"given":"Bonan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anatomical and Cellular Pathology State Key Laboratory of Translational Oncology Sir Y. 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