Core Viewpoint - The recent research highlights the role of tertiary lymphoid structures (TLS) in enhancing anti-tumor immunity and their prognostic value in cancer immunotherapy, emphasizing the need to understand the mechanisms driving TLS formation and to develop strategies to induce TLS for effective anti-tumor therapies [2][6]. Group 1: Research Findings - A study published in *Cancer Cell* reveals that IGLL5 B cell subpopulation disrupts TLS formation and suppresses anti-tumor immunity, particularly in bladder cancer, providing a potential new target for immunotherapy [3][10]. - The research identified an IGLL5+ B cell subpopulation in bladder cancer through single-cell RNA sequencing and spatial transcriptomics [7]. - In engineered humanized mouse models, IGLL5+ B cells compromised the integrity of TLS and weakened the response to immunotherapy [8]. Group 2: Mechanisms and Implications - The mechanism involves IGLL5+ B cells interacting with high endothelial venules (HEV) via IGLL5-LTβR, leading to conformational changes in LTβR that inhibit the non-canonical NF-κB signaling pathway, ultimately resulting in TLS disintegration [8]. - Preclinical studies indicate that blocking IGLL5 can maintain TLS and enhance the efficacy of immunotherapy in patient-derived xenograft models and pan-cancer models [9]. - Targeting IGLL5+ B cells presents a new strategy for enhancing TLS-dependent cancer immunotherapy [10].