2. Academic Validation
  3. B cells disrupt tertiary lymphoid structure formation and suppress anti-tumor immunity

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

  • Cancer Cell. 2026 Mar 9;44(3):551-566.e17. doi: 10.1016/j.ccell.2025.12.011.
Changhao Chen 1,  Mingjie An 2,  Hanhao Zheng 2,  Mingrui Pang 2,  Yuanlong Li 2,  Xiayao Diao 3,  Yuming Luo 4,  Yan Lin 2,  Daiyin Liu 2,  Wenjie Li 2,  Jiancheng Chen 2,  Zhicong Liu 2,  Zewei Chen 2,  Anhong Hu 2,  Wenlong Zhong 2,  Jian Huang 2,  Tianxin Lin 5
Affiliations

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: [email protected].
  • 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: [email protected].
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.

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