Researchers have identified a specific IGLL5+ B cell subset that drives resistance to immunotherapy in bladder cancer by undermining the integrity of tertiary lymphoid structures (TLSs). These specialized B cells preferentially anchor to high endothelial venules (HEVs), where the IGLL5 protein acts as an inhibitory ligand for the LTβR receptor. This interaction triggers a conformational change that suppresses non-canonical NF-κB signaling, causing HEVs to dilate and lose their ability to recruit essential anti-tumor lymphocytes. Consequently, the destruction of the TLS microenvironment prevents the activation of effector CD8+ T cells, leading to poor clinical outcomes. Experimental models demonstrate that targeting IGLL5 with neutralizing antibodies can restore TLS formation and significantly improve the efficacy of immune checkpoint blockade therapies. This discovery highlights the IGLL5-LTβR axis as a critical immune checkpoint and a promising therapeutic target for overcoming treatment resistance in multiple cancer types.

References:

• Chen C, An M, Zheng H, et al. B cells disrupt tertiary lymphoid structure formation and suppress anti-tumor immunity[J]. Cancer Cell, 2026.