SSR4 sustains Tertiary Lymphoid Structures by Regulation Quality Control of N‐linked Glycosylation During B‐cell Differentiation Into Plasmacyte in Colorectal Cancer

ABSTRACT Intratumoral tertiary lymphoid structure (TLS) fosters B‐cell differentiation and antibody production, yet the intrinsic programs sustaining these functions remain unclear. By integrating spatial transcriptomics and single‐cell RNA sequencing of colorectal cancer, we delineate a B‐cell trajectory enriched for endoplasmic reticulum protein processing, autophagy, NF‐κB signaling, and N‐linked glycosylation, highlighting SSR4 as a progressively induced TRAP‐complex component. SSR4 is further upregulated in B cells from anti‐PD‐1 responders. B‐cell‐specific Ssr4 deletion leads to peripheral B‐cell loss, reduced antibody output, exacerbated colitis, and impaired mucosal immunity. Mechanistically, SSR4 interacts with DDOST to regulate BAFFR N‐glycosylation, thereby sustaining B‐cell activation and LTα1β2 expression via NF‐κB signaling. In Apc ^Min/+ mice, Ssr4 deficiency accelerates tumorigenesis, disrupts TLS maturation, lowers serum IgG1, and increases high‐mannose (HM) Ig. Conversely, SSR4 overexpression in CHO cells reduces high‐mannose glycans and enhances IgG1 ADCC and CDC. These findings identify SSR4 as a central regulator of B‐cell glycosylation and TLS‐dependent anti‐tumor immunity, offering translational implications for immunotherapy and antibody engineering.