Decoding IGLL5 Mutation‐Mediated BCR Signaling: A Novel Mechanism of CD8 ⁺ T Cell Exhaustion and Ocular MALT Lymphoma Progression

ABSTRACT Ocular adnexal mucosa‐associated lymphoid tissue lymphoma (OAML) is driven by both genetic and immune microenvironmental factors, yet its pathogenic mechanisms remain incompletely understood. We previously identified IGLL5 as a recurrently mutated gene associated with poor prognosis in OAML. Functional and mechanistic analyses focusing on the S47G and A54G mutants show that these variants enhance association with the CD79A/CD79B complex, leading to persistent B‐cell receptor (BCR) signaling. This signaling is accompanied by upregulation of CXCL10 and CXCL11, increased CD8 ⁺ T cell recruitment, and an exhaustion‐associated dysfunctional phenotype that may contribute to an immune‐tolerant microenvironment. Pharmacologic inhibition further shows that combined BTK inhibitor and rituximab treatment suppresses IGLL5‐associated BCR activation. Together, these findings support a mutation‐associated mechanism in a subset of OAML and nominate IGLL5‐related signaling as a potential therapeutic vulnerability.