Targeting the Neuro-Immune Axis in Next-Generation Oncology: Discovery and Validation of β2-Adrenergic Blockade to Reverse Ecosystem-Wide Resistance.

Abstract

Despite the potential of current cancer immunotherapies, tumor cells frequently evade immune surveillance by forming an immunosuppressive microenvironment, leading to treatment resistance. Current inquiry positions the sympathetic nervous system (SNS) at the forefront of tumor immunology as a critical driver of this immune evasion. This review delineates the cellular pharmacology of SNS-mediated immune regulation across the tumor ecosystem. Operating predominantly through the cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) signaling axis, the SNS engages in bidirectional regulation with immune cells of the tumor microenvironment (TME). Norepinephrine and epinephrine interact with β₂-adrenergic receptors (β₂-ARs), triggering G-protein dissociation, adenylyl cyclase stimulation, and cAMP generation. This pharmacological cascade promotes the polarization of macrophages to the M2 phenotype, hinders dendritic cell maturation, impairs natural killer (NK) cell function, fosters the differentiation of regulatory T cells (Tregs), and suppresses the effector activity of CD8⁺ T cells. Consequently, we evaluate the translational prospects of repurposing β-blockers as potent anti-cancer immunomodulators. Preclinical evidence demonstrates that pharmacological blockade of β₂-AR signaling can reverse these immunosuppressive effects, augmenting intratumoral CD8⁺ T-cell infiltration and enhancing the efficacy of immune checkpoint inhibitors (ICIs). Ultimately, engineering multimodal combination regimens-guided by multi-omics biomarker stratification-offers a novel trajectory to overcome resistance, restore therapeutic sensitivity, and advance precision cancer immunotherapy.