B cells disrupt tertiary lymphoid structure formation and suppress anti-tumor immunity

Changhao Chen; Mingjie An; Hanhao Zheng; Mingrui Pang; Yuanlong Li; Xiayao Diao; Yuming Luo; Yan Lin; Daiyin Liu; Wenjie Li; Jiancheng Chen; Zhicong Liu; Zewei Chen; Anhong Hu; Wenlong Zhong; Jian Huang; Tianxin Lin

doi:10.1016/j.ccell.2025.12.011

B cells disrupt tertiary lymphoid structure formation and suppress anti-tumor immunity

Cancer Cell. 2026 Jan 8:S1535-6108(25)00545-8. doi: 10.1016/j.ccell.2025.12.011. Online ahead of print.

Authors

Changhao Chen¹, Mingjie An², Hanhao Zheng², Mingrui Pang², Yuanlong Li², Xiayao Diao³, Yuming Luo⁴, Yan Lin², Daiyin Liu², Wenjie Li², Jiancheng Chen², Zhicong Liu², Zewei Chen², Anhong Hu², Wenlong Zhong², Jian Huang², Tianxin Lin⁵

Affiliations

¹ Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, P.R. China. Electronic address: chenchh53@mail.sysu.edu.cn.
² Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, P.R. China.
³ Department of Thoracic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
⁴ Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China.
⁵ Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, P.R. China. Electronic address: lintx@mail.sysu.edu.cn.

PMID: 41512868
DOI: 10.1016/j.ccell.2025.12.011

Abstract

Tertiary lymphoid structures (TLSs) promote antigen-specific anti-tumor immunity, but the regulators of TLSs homeostasis in cancer remain unclear. Using single-cell RNA-sequencing and spatial transcriptomics, we identify an IGLL5⁺ B cell subset in bladder cancer (BCa). In genetically engineered and humanized mouse models, these IGLL5⁺ B cells disrupt TLS's integrity and impair immunotherapy responses. Mechanistically, IGLL5⁺ B cells bind high endothelial venules (HEVs) via IGLL5-LTβR ligand-receptor interactions, with IGLL5 inducing a conformational change in LTβR that inhibits non-canonical NF-κB signaling, leading to TLSs disassembly. Clinically, blocking IGLL5 preserves TLSs and enhances immunotherapy efficacy in patient-derived xenograft (PDX) and pan-cancer models. Our findings suggest that targeting IGLL5⁺ B cells offers a promising strategy to boost TLS-dependent cancer immunotherapy.

Keywords: IGLL5(+) B cells; LTβR; bladder cancer; high endothelial venules; immunotherapy; tertiary lymphoid structures.