Propranolol attenuates social isolation-associated anxiety-like behavior, immune dysfunction, and melanoma progression in mice, with involvement of β-adrenergic signaling

Abstract

Chronic psychosocial stress, such as social isolation, is highly prevalent among cancer patients and has been associated with emotional disturbances including anxiety and depression as well as accelerated tumor progression and immune evasion through systemic remodeling of the neuro-endocrine-immune network. However, the key molecular bridge and actionable targets remain incompletely elucidated. In this study, using a murine model of social isolation stress established by 4-week single-cage housing in male C57BL/6 mice bearing B16F10 melanoma cells in the footpad, we investigated the role of β₂-adrenergic receptor (β₂-AR) signaling in stress-induced anxiety-like behaviors and tumor immunosuppression. Our results demonstrated that socially isolated mice exhibited anxiety-like phenotypes, characterized by decreased exploration in the central zone of the open field and decreased open arm entries and time in the elevated plus maze, accompanied by lower serum norepinephrine and corticosterone levels, suggesting neuroendocrine alterations under prolonged chronic stress. Concurrently, tumor growth was accelerated in isolated mice, with decreased intratumoral CD8⁺ leukocyte infiltration and secretion of IFN-γ and granzyme B, as well as decreased splenic CD8⁺ leukocyte counts, whereas protein expression of β₂-AR, SOX10, and PD-L1 in tumor tissues was upregulated. Administration of the non-selective β-blocker propranolol (40 mg/kg, intragastric gavage for 8 days) was associated with improved anxiety behaviors, restored endocrine parameters, increased CD8⁺ leukocyte effector functions, decreased SOX10/PD-L1 expression, and reduced tumor growth while increasing thymic weight. However, co-administration of the β-adrenergic agonist isoproterenol (2 mg/kg/d, intraperitoneal injection) attenuated the effects of propranolol, with re-emergence of anxiety manifestations, immunosuppression, and rapid tumor progression, consistent with the involvement of β-adrenergic signaling. Collectively, social isolation stress is associated with melanoma progression and immune alterations via altered β₂-AR-mediated SOX10–PD-L1 expression while also being associated with anxiety-related behaviors; propranolol, through β-adrenergic blockade, demonstrated effects on emotional regulation and antitumor immune function, providing a preclinical basis for further investigation in melanoma patients with significant social isolation and psychological distress.