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.