Targeting the G-protein–coupled estrogen receptor: a novel therapeutic strategy in cutaneous T-cell lymphoma

• The selective GPER agonist G-1 induces growth arrest and apoptosis in malignant T cells while largely sparing normal lymphocytes. • G-1 effectively limits CTCL tumor progression in vivo, highlighting GPER signaling as a promising therapeutic approach. Cutaneous T-cell lymphoma (CTCL) represents a heterogeneous group of non-Hodgkin lymphomas with limited curative treatment options. The pronounced male predominance in CTCL incidence suggests hormonal influences in disease pathogenesis, prompting investigation into estrogen receptor signaling pathways as therapeutic targets. Building upon previous evidence of tumor-suppressive roles of estrogen signaling via estrogen receptor β (ERβ), we investigated the therapeutic potential of targeting the G protein-coupled estrogen receptor (GPER) in CTCL models. We evaluated the anti-tumor effects of G-1, a selective GPER agonist, in CTCL cell lines and primary patient-derived malignant T cells using in vitro and in vivo approaches. G-1 demonstrated robust dose-dependent cytotoxic effects against CTCL cells, with notable selectivity, as healthy CD4 + T lymphocytes were largely unaffected. Mechanistically, G-1 induced G 2 /M arrest and apoptosis, involving activation of DNA damage responses and extrinsic apoptotic signaling, along with suppression of proliferative and survival pathways, including c-Myc and NF-κB. In vivo validation using a MyLa xenograft model demonstrated significant tumor growth inhibition following G-1 treatment without toxicity. These findings position GPER as a promising therapeutic target in CTCL and support further development of GPER-targeted strategies for treating cutaneous T-cell lymphomas.