Targeting the β₂-adrenergic receptor suppresses melanoma progression by disrupting the PKA-SOX10-MAGEA1 oncogenic...

Chronic stress and sympathetic signaling, mediated by the β₂-adrenergic receptor (ADRB2), are implicated in cancer progression. In melanoma, a neural crest-derived malignancy, the interplay between neuroendocrine signals and tumor cell plasticity remains poorly understood. Elucidating how ADRB2 activation translates into pro-tumorigenic transcriptional programs is crucial for developing novel therapeutics. We combined genetic and pharmacological ADRB2 modulation in melanoma models with transcriptomics, mechanistic assays, and patient sample analysis. ADRB2 inhibition suppressed tumor growth by arresting the cell cycle and inducing apoptosis. Transcriptomic analysis revealed MAGEA1 as the most downregulated gene upon ADRB2 knockout. Mechanistically, ADRB2 signaling via the PKA pathway upregulated and promoted the nuclear translocation of the transcription factor SOX10. SOX10, in turn, directly bound to the MAGEA1 promoter to drive its transcription. In clinical specimens, high expression of ADRB2, SOX10, and MAGEA1 correlated with poorer patient prognosis. Our study defines a novel ADRB2-PKA-SOX10-MAGEA1 signaling axis that critically promotes melanoma growth. This axis positions ADRB2 as a key node linking neuroendocrine stress signals to the core transcriptional machinery governing melanoma cell proliferation and survival. Targeting ADRB2 presents a promising therapeutic strategy to counteract stress-induced melanoma progression.