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REVIEW

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

Heng Xu1,#, Jiaan Lu1,#, Zizhang Wang1,#, Jiayu Xu2, Shihui Peng3, Haiqing Chen4, Qiang Cao5,*, Qing Sun6,*, Shangke Huang7,*
1 Clinical Medical College, Southwest Medical University, Luzhou, China
2 School of Computer Science and Informatics, Cardiff University, Cardiff, UK
3 Department of Public Health Laboratory Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China
4 Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
5 Faculty of Applied Sciences, Macao Polytechnic University, R. de Luís Gonzaga Gomes, Macao, China
6 Department of Otolaryngology, QingPu Hospital Affiliated to Fudan University, Shanghai, China
7 Department of Oncology, The Affiliated Hospital, Southwest Medical University, Luzhou, China
* Corresponding Author: Qiang Cao. Email: email; Qing Sun. Email: email; Shangke Huang. Email: email
# These authors contributed equally to this work
(This article belongs to the Special Issue: Next-Generation Oncology: Unearthing and Validating Novel Therapeutic Targets)

Oncology Research https://doi.org/10.32604/or.2026.083919

Received 13 April 2026; Accepted 25 May 2026; Published online 15 June 2026

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.

Keywords

Predictive biomarkers; multi-omics; sympathetic-immune axis; tumor ecosystem; immunotherapy resistance; β2-adrenergic receptor; clinical translation

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