Cell type-specific pharmacological modulation of the neuro-immune axis: the role of ADRB2 signaling in reshaping the tumor ecosystem

Adrenergic signaling through β2-adrenergic receptor (ADRB2) is a conserved neuro-immune axis that modulates tumor biology at multiple levels: tumor cells, stromal compartments (CAF, endothelium), myeloid populations (MDSC/TAM), and lymphocytes (CD4 + /CD8 + ). Activation of ADRB2 by stress-related catecholamines (norepinephrine/epinephrine) promotes angiogenesis, pro-metastatic programs and immunosuppression; conversely, ADRB2 blockade in preclinical models reprograms myeloid cells, potentiates T cell-mediated antitumor immunity and synergizes with immune checkpoint blockade in defined contexts. Clinical and epidemiologic data remained heterogeneous, but other small randomized and retrospective studies suggested that short-term pharmacologic suppression of adrenergic signaling (often combined with COX-2 inhibition) can favorably affect biomarkers and, in pilot trials, disease-free survival. This review summarized cell type-specific mechanisms linking ADRB2 to tumor ecosystem remodeling, compared pharmacological strategies for selective and cell-directed ADRB2 modulation, and outlined translational priorities and trial designs to move ADRB2-targeted approaches into practice.