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

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.