Beta-Blockers on Neoadjuvant Immunochemotherapy for Hypertensive Patients With Gastric Cancer (BNIHGC)

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.

Numerous basic experiments and clinical studies have verified the anti-tumor activity of BBs: non-selective beta-blockers can inhibit the proliferation of gastric cancer cells and induce apoptosis in animal models; catecholamines released by host sympathetic activation can suppress CD8⁺ T cell activity via ADRB-mediated cAMP/PKA signaling, while BBs can enhance the efficacy of PD-1 inhibitors by upregulating PD-L1 expression on tumor-associated macrophages and blocking the synergistic inhibitory signals of the LRRC33/TGFβ1 axis and PD-1. In head and neck squamous cell carcinoma and non-small cell lung cancer, the combination of BBs and immunotherapy can improve patient survival, but relevant clinical data in gastric cancer remain limited.

Our team previously enrolled 25 eligible patients from 5 hospitals across China, all of whom underwent radical resection. The distribution of postoperative pathological tumor regression grade (TRG) was as follows: TRG 0 in 10 patients (40%), TRG 1 in 4 patients (16%), TRG 2 in 11 patients (44%), and TRG 3 in 0 patients. The proportion of TRG 0/1 (pathological complete or near-complete response) was 56% (14/25), comparable to the immunotherapy plus chemotherapy group of the NEOSUMMIT-01 study; the proportion of TRG 3 (pathological non-response) was 0, significantly lower than the same group of the NEOSUMMIT-01 study. No serious beta-blocker-related adverse events were observed during treatment in the cohort.

Based on the above research background and unresolved questions, this study intends to use a nationwide multicenter retrospective cohort data of advanced GC patients with primary hypertension, compare the efficacy of beta-blockers versus non-beta-blocker antihypertensive agents during immunotherapy, and systematically evaluate the unique synergistic effect of beta-blockers. This study aims to provide high-level evidence for combination immunotherapy strategies in GC patients with hypertension, and promote the development of neuro-immuno-oncology in gastric cancer, opening a new avenue to improve the prognosis of this special patient population.

Study Objectives 2.1 Primary Objective To investigate the impact of combined use of beta-blockers (compared with non-beta-blocker antihypertensive agents) on the efficacy of immunotherapy in patients with advanced gastric cancer complicated by primary hypertension.

2.2 Secondary Objective To investigate the impact of combined use of beta-blockers (compared with non-beta-blocker antihypertensive agents) on the incidence of immune-related adverse events (irAEs).

Study Design This is a retrospective, multicenter, observational study. Eligible gastric cancer patients with primary hypertension who received neoadjuvant chemoradiotherapy combined with immunotherapy followed by gastrectomy at Nanfang Hospital of Southern Medical University and other participating centers between April 2021 and December 2025, with complete follow-up data, will be enrolled.

Patients will be divided into an exposed group and a non-exposed group according to the use of beta-blockers antihypertensive drugs during immunotherapy:

• Exposed group: Patients who continuously used beta-blockers during neoadjuvant immunochemotherapy
• Control group: Patients who continuously received non-beta-blocker antihypertensive agents (e.g., ACEI/ARB/CCB, diuretics, observation) during the same period Propensity score matching (PSM) will be used to control baseline confounding factors, including age, metastatic burden, CPS score, number of immunotherapy cycles, and hypertension grade.

No randomization or study protocol-driven treatment will be administered to participants. All treatment decisions and regimens will be determined by the treating physician based on clinical indications.

Study Population The study population consists of patients with locally advanced gastric cancer complicated by hypertension who are scheduled to undergo laparoscopic gastrectomy after immunotherapy.

4.1 Diagnostic Criteria

• Gastric cancer diagnosed in accordance with the 15th edition of the Japanese Classification of Gastric Carcinoma (2017)
• Hypertension diagnosed in accordance with the Chinese Guidelines for the Prevention and Treatment of Hypertension 2023 (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg)

Inclusion and Exclusion Criteria 5.1 Inclusion Criteria

• Age 18-85 years
• No gender restriction
• Histopathologically confirmed gastric adenocarcinoma from the primary gastric lesion via endoscopic biopsy, according to the 15th edition of the Japanese Classification of Gastric Carcinoma(2017)
• Patients who received neoadjuvant immunochemotherapy followed by gastrectomy at Nanfang Hospital of Southern Medical University and other participating centers between April 2021 and December 2025 5.2 Exclusion Criteria
• Pregnant or breastfeeding women
• Severe psychiatric disorders
• Previous history of chemotherapy, radiotherapy, or targeted therapy
• History of other malignant tumors within the past 5 years
• dMMR or MSI-H status determined by immunohistochemistry or PCR-based assays
• Active infection, active or refractory autoimmune disease, or uncontrolled systemic disease
• Patients judged by the investigator to be unsuitable for this study

Data Collection Procedures

Data collection will be conducted in three phases:

7.1 Baseline Phase (First Patient Visit)

• Demographic data: gender, age, patient initials
• Medical history and physical examination: height, weight, BMI, underlying diseases, ID number, hospital record number, operation date 7.2 Routine Diagnosis and Treatment Phase
• Laboratory test results: pathological tumor stage, pathological type, histological type, tumor size, tumor location, pathological TRG grade, immunotherapy-related immunohistochemical indicators (CPS, EBER, HER2, PMS2, MLH1, MSH2, MSH6)
• Imaging findings: abdominal computed tomography (CT)
• Antihypertensive medication data: start time, duration, type and dosage of beta-blockers and non-beta-blocker antihypertensive agents 7.3 Follow-up Phase A 3-year telephone follow-up will be performed once a year to record overall survival (OS) and recurrence-free survival (RFS).