Beta-blockers Combined With Neoadjuvant Immunochemotherapy Significantly Improve Pathological Remission in Locally Advanced Gastric Cancer: a Multicenter Controlled Study Based on Hypertensive Patients

1. Research Background 1.1 Disease Burden of Gastric Cancer, Hypertension Comorbidity and Treatment Challenges Gastric carcinoma (GC) is one of the most common malignant tumors worldwide, ranking fifth in incidence and fourth in mortality globally. A large proportion of GC patients in China are diagnosed at an advanced stage, leading to short survival and poor quality of life. Notably, hypertension is one of the most prevalent comorbidities in advanced GC patients, with clinical data showing that approximately 30%-40% of such patients have primary hypertension. These patients not only face difficulties in blood pressure control due to excessive sympathetic nervous system activation, but also suffer from a deteriorated tumor microenvironment caused by abnormal neuro-immune crosstalk.

In recent years, immune checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitors) have brought new hope for advanced GC treatment by relieving tumor-induced immune suppression and activating the body's anti-tumor immune response, demonstrating significant efficacy in a subset of patients. However, only 10%-15% of GC patients achieve long-term benefits from current immunotherapy, and the response rate may be even lower in patients with hypertension due to sympathetic activation. Most patients still develop primary or acquired resistance. This low response rate has driven research into combination strategies to enhance immunotherapy efficacy, and the potential immunomodulatory effects of beta-blockers (BBs), a commonly used antihypertensive drug, have become a research focus.

1.2 Core Role of Sympathetic Nervous System Regulation in the Tumor Microenvironment and the Impact of Hypertension With advances in tumor immunology, the immunosuppressive role of the sympathetic nervous system in the tumor microenvironment has been gradually revealed. In GC patients with hypertension, persistent excessive sympathetic activation caused by long-term abnormal blood pressure releases large amounts of catecholamine neurotransmitters (mainly norepinephrine), forming a tumor immunosuppressive cycle that critically impairs immunotherapy efficacy.

Basic research has confirmed that norepinephrine participates in tumor immune escape by binding to β-adrenergic receptors (ADRBs, especially the ADRB1 subtype) on immune cells. A 2024 study published in *Nature* by the Salk Institute revealed that exhausted CD8⁺ cytotoxic T cells highly express ADRB1, making them highly sensitive to norepinephrine, which inhibits T cell proliferation and reduces effector molecule secretion, ultimately leading to T cell exhaustion. A landmark study in *Science* further elucidated this mechanism: norepinephrine activates the cAMP/PKA signaling pathway through ADRB1, inducing high expression of exhaustion markers such as PD-1 and TIM-3 on T cells and weakening anti-tumor immune responses. Beta-blockers can competitively block ADRB1 and reverse T cell exhaustion, providing direct mechanistic support for their combination with immunotherapy. In addition, the nerve density in gastric cancer tissues is significantly higher than that in normal tissues, and increased catecholamine release in patients with hypertension further enhances ADRB-mediated immunosuppression and exacerbates T cell exhaustion, laying an important theoretical foundation for targeting the β-receptor pathway.

1.3 Anti-Tumor Mechanisms, Clinical Evidence of Beta-Blockers and Research Gaps As classic cardiovascular drugs, beta-blockers are mainly used for the treatment of primary hypertension. By blocking β-adrenergic receptors to inhibit excessive catecholamine signaling, they not only control blood pressure but also exert potential anti-tumor effects by regulating immunosuppressive pathways in the tumor microenvironment.