IL-2/IL-2Rβγ signaling in pruriceptors drives neuroimmune mechanisms of nivolumab-induced persistent itch

Immune checkpoint inhibitor (ICI) therapy frequently induces pruritus as a cutaneous immune-related adverse event, affecting 13–25% of patients treated with anti–PD-1 antibodies. Unlike allergy-associated itch, ICI-induced pruritus often responds poorly to antihistamines, indicating a distinct mechanism. This study aimed to investigate the mechanisms by which repeated PD-1 blockade induces persistent itch and to identify molecular pathways linking immune activation with pruriceptor sensitization. We established a mouse model of pruritus by repeated administration of Nivolumab subcutaneously. Behavioral assays were conducted to evaluate itch-like behaviors (scratching). The expression and distribution of IL-2 receptor subunits in dorsal root ganglia (DRG) were assessed using qPCR, RNAscope, and Western blotting. Electrophysiological recordings, fluorescent antibody labeling, immunostaining, and pharmacological interventions were employed to explore the cellular and molecular mechanisms. A single Nivolumab injection induced transient scratching, whereas three consecutive injections triggered persistent itch lasting about one week beyond drug withdrawal. Persistent itch was accompanied by dermal CD4⁺ T-cell infiltration and elevated serum IL-2. Neutralization of IL-2 abolished persistent but not transient itch. In DRG, repeated Nivolumab selectively upregulated IL-2 receptor β and γ subunits, localized predominantly to MrgprA3⁺ pruriceptors. These neurons exhibited enhanced excitability, c-Fos induction, and direct Nivolumab binding. Mechanistically, PD-1 blockade suppressed SHP-1 phosphorylation, promoted JNK and STAT5 activation, and drove IL-2Rβ/γ upregulation. JNK inhibition prevented IL-2R induction and alleviated persistent itch without affecting acute responses. Our findings demonstrate that repeated Nivolumab administration upregulates IL-2Rβ/γ in MrgprA3⁺ neurons via SHP-1–JNK–STAT5 signaling, together with elevated systemic IL-2, establishing a neuroimmune loop that drives ICI-induced pruritus.