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

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.