LY18 Lymphocyte activation gene 3 in cutaneous T-cell lymphomas: from tumour microenvironment regulation to potential therapeutic targeting

Abstract

Lymphocyte activation gene 3 (LAG-3; CD223) is an inhibitory immune checkpoint receptor that regulates T-cell activation and contributes to immune tolerance. In cancer, LAG-3 is frequently coexpressed with programmed cell death protein-1 (PD-1) on exhausted tumour-infiltrating lymphocytes, and its blockade has emerged as a promising immunotherapeutic strategy. Cutaneous T-cell lymphomas (CTCLs), including mycosis fungoides (MF) and Sézary syndrome (SS), are characterized by profound immune dysregulation, T-cell exhaustion and tumour microenvironment-­driven immune escape, providing a strong rationale for checkpoint-based therapies. However, clinical responses to PD-1 inhibition in CTCL remain limited, prompting interest in alternative or complementary targets such as LAG-3. This review summarizes current evidence on the expression, regulation and functional role of LAG-3 in CTCL. Available data indicate that LAG-3 expression is heterogeneous and highly context dependent. In MF, LAG-3 is detectable on subsets of CD4+ and CD8+ tumour-infiltrating lymphocytes and regulatory T cells, where it may contribute to local immunosuppression within skin lesions. In contrast, SS is characterized by systemic downregulation of LAG-3 in peripheral blood T cells, despite upregulation of other inhibitory receptors, highlighting distinct compartment-specific immune landscapes. Genetic studies further suggest that germline LAG-3 variants may influence MF susceptibility by modulating tissue-resident memory T-cell function. Overall, LAG-3 does not appear to be a dominant checkpoint in CTCL but rather a modulatory component of a complex, multicellular exhaustion network shaped by microenvironmental cues. Its inducible expression in defined contexts supports the potential for patient-stratified and combinatorial immunotherapeutic approaches. Future mechanistic and protein-level studies are needed to clarify the therapeutic relevance of LAG-3 targeting in CTCL.