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Background Sézary syndrome (SS) is a rare and aggressive cutaneous T-cell lymphoma characterized by the clonal proliferation of malignant CD4 + T cells (Sézary cells, SCs) in the blood, skin, and lymph nodes. Despite existing therapies, many patients have poor prognosis and face relapse or resistance. SCs are known to co-express several immune markers and their ligands, prompting investigation into the ICOS/ICOSL axis, a key pathway in T cell activation. Our study aimed to characterize ICOS/ICOSL expression in SS and assess its potential as a therapeutic target.Methods ICOS and ICOSL expression were examined in SS patient samples, SS-derived cell lines, and other T-cell lymphoma subtypes. ICOSL isoform analysis was performed to identify variants and their structural features, using RT-PCR, Westernblot, and Sanger sequencing. Functional assays assessed the effects of ICOS-ICOSL engagement or blockade on cell viability, AKT phosphorylation, and signalling pathways. An ICOS-Fc fusion protein, that can bind to all ICOSL isoforms, was tested for its ability to induce tumor clearance via antibody-dependent cell cytotoxicity (ADCC).Results Sézary cells aberrantly co-express both ICOS and ICOSL. Notably, two ICOSL isoforms, ICOSL4.1 and ICOSL4.2 were identified having distinct cytoplasmic domains, suggesting they may engage different intracellular signaling pathways. Engagement of ICOSL led to activation of the pro-survival AKT signaling pathway, whereas blockade of the ICOS/ICOSL axis enhanced tumor cell death. Therapeutic targeting of ICOSL with ICOS-Fc promoted immune-mediated tumor clearance driven by natural killer (NK) cell recruitment and ADCC.Conclusions We demonstrate that SCs co-express ICOS and ICOSL, enabling a cis/trans interactions that activate the pro-survival AKT pathway. Therapeutic targeting of this axis with ICOS-Fc induces immune-mediated tumor depletion. These findings position ICOSL as a novel and druggable therapeutic target in SS, offering a promising strategy for treating a malignancy with urgent unmet clinical needs.Ethics Approval This study has been approved by the French Ethics Committee in 2019 (number 2019-A01158-49), and donors of human materials have provided written informed consent.