Bloqueadores Beta sobre la Eficacia de la Inmunoterapia Neoadyuvante para el Cáncer Gástrico (BBNIGC)

1. Research Background

1. Disease Burden of Gastric Cancer and Current Treatment Challenges

   Gastric carcinoma (GC) is one of the most common malignant tumors globally, ranking fifth in incidence and fourth in mortality worldwide. Gastric cancer patients in China often present with advanced stage at diagnosis. Many are already at a progressive or advanced stage upon diagnosis, resulting in short survival times and poor quality of life. In recent years, tumor immunotherapy, particularly immune checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitors), has brought new hope for gastric cancer treatment. These therapies work by relieving the suppression of immune cells by the tumor and activating the patient's own anti-tumor immune response, demonstrating significant efficacy in some gastric cancer patients. However, clinical practice indicates that only about 10%-15% of gastric cancer patients achieve long-term benefit from existing immunotherapy; the majority still face primary or acquired resistance [1]. This situation of low response rates has driven in-depth research into the immunosuppressive mechanisms within the tumor microenvironment [2] and the search for combination strategies that can enhance the effectiveness of immunotherapy.

2. The Core Role of Sympathetic Nervous System Regulation in the Tumor Microenvironment

   With advances in tumor immunology, the role of the sympathetic nervous system in the tumor microenvironment is gradually being revealed. Clinical observations have found that gastric cancer patients with baseline anxiety (GAD-7 ≥5) or depression (PHQ-9 ≥5) have a significantly lower rate of achieving pathological significant response (TRG 0-2) after immunotherapy. The core driving factor is the chronic stress state reflected by anxiety-including the physiological and psychological stress from the disease itself and treatment-related anxiety-rather than the anxiety symptoms themselves. When the body is in this state, the sympathetic nervous system is overactivated, releasing large amounts of catecholamine neurotransmitters (primarily norepinephrine and epinephrine), initiating the classic "fight-or-flight" response. In the tumor environment, this response becomes a key driver of immunotherapy resistance by regulating immune function.

   Basic research has confirmed that catecholamines elevated by chronic stress play a critical role in tumor immune evasion by binding to β-adrenergic receptors (ADRBs) on the surface of immune cells, particularly the ADRB1 and ADRB2 subtypes highly expressed on CD8⁺ T cells [3]. Specifically, the binding of catecholamines to ADRB1/ADRB2 activates the downstream cAMP/PKA signaling pathway, which, on one hand, inhibits metabolic reprogramming of CD8⁺ T cells (reducing glucose uptake and glycolysis), and on the other hand, promotes the expression of exhaustion markers like PD-1, forming a positive feedback loop [2, 3]. This leads to severe suppression of T cell function, manifested as impaired cell proliferation, reduced secretion of effector molecules (e.g., perforin, granzyme B), and impaired immune memory formation. Ultimately, this results in T cell "exhaustion," rendering them unable to effectively respond to the activation signals of immune checkpoint inhibitors. This is the core biological mechanism underlying the difference in immunotherapy efficacy between patients with and without anxiety [3, 14].

   This mechanism is particularly prominent in the gastric cancer microenvironment: the nerve density in gastric cancer tissues is significantly higher than in normal tissues. In diffuse-type gastric cancer, ADRB2 expression is significantly positively correlated with tumor nerve density. Patients with high ADRB2 expression have more severe lymph node metastasis [4], and the inflammatory response mediated by perineural invasion (PNI) further amplifies the immunosuppressive effects of catecholamines [4], providing a gastric cancer-specific theoretical basis for targeting this pathway.

   The nerve density in gastric cancer tissues is significantly higher than in normal tissues, and the degree of nerve infiltration is closely associated with poor prognosis [4]. A research team at Heidelberg University Hospital confirmed through immunohistochemical analysis that in diffuse-type gastric cancer, ADRB2 expression levels are significantly positively correlated with the neural marker PGP9.5, and patients with high expression often have more severe lymph node metastasis (advanced ypN stage). This discovery highlights the central role of adrenergic signaling in gastric cancer neurogenesis and malignant progression, providing a theoretical basis for targeting this pathway.

3. Anti-tumor Mechanisms and Clinical Evidence of Beta-Blockers

Beta-blockers (BBs), a classic class of cardiovascular drugs, have long been used to treat conditions such as hypertension, arrhythmias, and heart failure. Their core mechanism is competitive blockade of β-adrenergic receptors (ADRB1/ADRB2), inhibiting excessive catecholamine signaling. This study selects this class of drugs not for their anti-anxiety effects, but to target the "chronic stress-catecholamine-β-receptor" immunosuppressive pathway described above to enhance immunotherapy efficacy.

In recent years, numerous studies have confirmed that BBs possess tumor immunomodulatory activity [5, 6, 7, 8, 9], providing a strong rationale for their combination with immunotherapy: ① Mechanistically, BBs can block the catecholamine-mediated activation of the cAMP/PKA signaling pathway by occupying ADRB1/ADRB2 receptors on the surface of CD8⁺ T cells, thereby restoring T cell proliferation capacity and cytotoxic molecule (perforin, granzyme B) secretion, and reducing the expression of exhaustion markers like PD-1 [3, 11]; ② Gastric cancer-specific evidence shows that non-selective beta-blockers can inhibit gastric cancer cell proliferation and induce apoptosis in animal models [10], and can synergize with PD-1 inhibitors by upregulating PD-L1 expression on tumor-associated macrophages (TAMs) [12] or by blocking the synergistic inhibitory signals of the LRRC33/TGFβ1 axis with PD-1 [13].

In recent years, the value of beta-blockers (BBs) combined with immune checkpoint inhibitors (ICI) in enhancing efficacy has been validated across various tumor types, providing direct scientific rationale for exploration in the gastric cancer field. Key study data are as follows:

Non-Small Cell Lung Cancer (NSCLC): A retrospective study of 109 NSCLC patients treated with ICI showed that the 28 patients concurrently using beta-blockers had significantly prolonged progression-free survival (PFS), with a hazard ratio (HR) of 0.58 (95% CI: 0.36-0.93) [22].

Melanoma: A Phase I trial exploring the combination of a beta-blocker (propranolol) with pembrolizumab for locally advanced or metastatic melanoma reported an objective response rate (ORR) of 78% in 9 patients treated with various doses of propranolol (10/20/30 mg twice daily) [23]. This rate is notably higher than the approximately 45% ORR historically reported for pembrolizumab monotherapy.

Head and Neck Squamous Cell Carcinoma (HNSCC): A retrospective cohort study showed that HNSCC patients treated with ICI combined with beta-blockers had a 3-year overall survival (OS) rate 22% higher than the ICI monotherapy group (58% vs. 36%), with a 41% reduced risk of disease progression (HR=0.59, 95% CI: 0.38-0.92) [14].

This study selects the highly selective β1-receptor blocker metoprolol succinate. Its selectivity for ADRB1 over ADRB2 allows it to precisely target the ADRB1 receptor highly expressed on CD8⁺ T cells [3]. The extended-release formulation (47.5 mg/day) maintains stable plasma drug concentrations, continuously blocking the immunosuppressive pathway. Additionally, its extensive clinical use history with ample safety data, and good tolerability when combined with immunotherapy and chemotherapy, meets the requirements for long-term intervention.

Preliminary clinical studies conducted by our team directly focused on the impact of chronic stress on immunotherapy efficacy in gastric cancer, providing key clinical evidence. The research found that among gastric cancer patients receiving immunotherapy, those with significant baseline anxiety (GAD-7 ≥5) and depression (PHQ-9 ≥5) had a significantly lower rate of achieving pathological significant response (e.g., TRG 0-2) post-surgery compared to patients in good psychological condition. It is crucial to clarify that the core hypothesis of this study is not that "anxiety symptoms directly lead to poor immunotherapy outcomes," but rather that "the chronic stress state reflected by anxiety suppresses T cell function via the 'sympathetic nerve-catecholamine-β-receptor' pathway, ultimately reducing immunotherapy sensitivity." Anxiety is a key clinical manifestation of chronic stress, but not the direct cause of immune resistance.

Therefore, this study does not employ standardized anti-anxiety treatments like cognitive behavioral therapy (CBT). The core reasons are as follows:

Mismatch of Intervention Target and Study Objective: Standardized anti-anxiety treatments (e.g., CBT, anxiolytics) primarily aim to alleviate anxiety symptoms, not to block the immunosuppressive pathway mediated by chronic stress [18]. Even if a patient's anxiety symptoms improve, the sympathetic overactivation and elevated catecholamines caused by chronic stress may persist, failing to fundamentally restore T cell anti-tumor activity [3, 5]. Conversely, beta-blockers target the critical juncture of the immunosuppressive pathway (β-receptors), directly addressing the "T cell functional suppression" that is a core mechanism of immunotherapy resistance, which highly aligns with the study's primary objective of "enhancing immunotherapy efficacy" [3, 13].

Incompatibility of Onset Time and Therapeutic Window: The preoperative neoadjuvant immunotherapy cycle for gastric cancer is only 4 cycles (approximately 12 weeks), requiring effective modulation of immune pathways within a limited time to improve pathological response [19]. The onset time for standardized anti-anxiety treatments (e.g., CBT) is typically 8-12 weeks, with significant individual variability, making it difficult to rapidly block the activated immunosuppressive pathway within the preoperative treatment window [18]. In contrast, beta-blockers reach peak plasma concentration 1-2 hours after oral administration and can stably block β-receptor signals within 2-3 days, perfectly matching the timeline requirements of preoperative immunotherapy.

Differences in Scientific Evidence Supporting Efficacy: Currently, no clinical study has confirmed that "anti-anxiety treatment can improve immunotherapy efficacy in gastric cancer patients," and its regulatory effect on CD8⁺ T cell function and the tumor immune microenvironment lacks basic experimental support [18]. However, the mechanism of beta-blockers blocking the catecholamine-β-receptor pathway and restoring T cell function has been confirmed by multiple basic experiments [3, 11]. Furthermore, survival benefits of combining beta-blockers with immunotherapy have already been observed in non-small cell lung cancer and head and neck squamous cell carcinoma [14, 15], providing ample scientific evidence supporting their use for immunotherapy potentiation.

In summary, the choice of beta-blockers over standardized anti-anxiety treatments in this study is based on a comprehensive consideration of "precise target matching, compatible onset time, and sufficient evidence." The core logic is "targeting the immunosuppressive pathway" rather than "treating anxiety symptoms," consistent with the study's primary aim of enhancing the efficacy of immunotherapy for gastric cancer.

2. Study Objectives

2.1 Primary Objective: To investigate the impact of combined beta-blocker use on the efficacy of immunotherapy in patients with advanced gastric cancer.

2.2 Secondary Objective: To investigate the impact of combined beta-blocker use on the incidence of immune-related adverse events.

3. Study Endpoints

3.1 Primary Endpoint: Pathological response rate at 1 week post-surgery.

3.2 Secondary Endpoints: 3-year overall survival (OS), 3-year progression-free survival (PFS); correlation with immunotherapy-related biomarkers (e.g., PD-L1 expression, cortisol, adrenocorticotropic hormone, tumor tissue ADRB1 expression, tumor tissue RNA sequencing, tumor immune microenvironment); treatment compliance (immunotherapy completion rate, surgery delay rate); quality of life score (EORTC QLQ-C30); incidence of treatment-related adverse events (beta-blocker-related: bradycardia, hypotension; chemotherapy-related: neutropenia, thrombocytopenia, hand-foot syndrome).

4. Study Design

4.1 Overall Design

This clinical study is a prospective, single-center, exploratory, single-arm, uncontrolled trial. It will recruit gastric cancer patients scheduled to undergo radical gastrectomy after neoadjuvant therapy. After signing the informed consent form, patients meeting the inclusion criteria will be enrolled. All enrolled subjects will receive a unified treatment regimen:

Basic Treatment: 4 cycles of preoperative immunotherapy combined with chemotherapy (anti-PD-1 antibody + XELOX/SOX/Capoex regimen, every 3 weeks [Q3W]).

Intervention: During the 4 cycles, subjects will take a fixed daily dose of metoprolol succinate extended-release tablets (47.5 mg), continuing until the day before surgery.

A total of 33 subjects are planned for enrollment. Data, including tumor regression grade, imaging stage, and immunotherapy-related indicators, will be recorded for each subject before immunotherapy and before surgery. Subjects will be followed up for 3 years post-surgery.

4.2 Randomization and Blinding

4.2.1 Randomization As this is a single-arm, uncontrolled exploratory study, all subjects meeting the inclusion criteria will receive the same treatment regimen; no randomization into groups will be performed.

4.2.2 Blinding Given the single-arm design with no requirement for inter-group comparison, blinding for pathologists, radiologists, and follow-up evaluators will not be implemented.

5. Study Population

The study population consists of patients with locally advanced gastric cancer scheduled to undergo laparoscopic gastrectomy after immunotherapy.

5.1 Diagnostic Criteria: Patients diagnosed with gastric cancer according to the 15th edition of the Japanese Classification of Gastric Carcinoma (2017).

5.2 Inclusion Criteria:

Voluntarily sign the informed consent form;

Aged 18-75 years;

ECOG performance status 0-1;

Either sex;

Patients with a standardized histopathological diagnosis of gastric adenocarcinoma from the primary gastric lesion via endoscopic biopsy, according to the 15th edition of the Japanese Classification of Gastric Carcinoma (2017);

Patients judged by the treating physician to require preoperative immune checkpoint inhibitor therapy, followed by potentially curative gastrectomy;

Meet the diagnostic criteria for hypertension according to the 2023 Chinese Guidelines for the Management of Hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg, or a previous diagnosis of uncontrolled hypertension), with an indication for beta-blocker use;

Deemed by a specialist to have no contraindications for beta-blocker use and can use beta-blockers for antihypertensive therapy.

5.3 Exclusion Criteria:

HER2-positive or microsatellite instability-high (MSI-H)/dMMR gastric cancer confirmed by immunohistochemistry;

Active autoimmune disease requiring continuous immunosuppressive therapy or history of transplantation;

Currently receiving systemic immunosuppressive medication: If a patient is currently using corticosteroids, the corticosteroid dose must be ≤ equivalent of prednisone 10 mg daily;

History of (non-infectious) pneumonitis/interstitial lung disease requiring treatment;

Concurrent infection with human immunodeficiency virus (HIV);

Pregnant or breastfeeding women;

History of psychiatric disorders;

Concurrent other malignancies or severe organ dysfunction;

Presence of contraindications for beta-blocker use (e.g., severe bradycardia, uncontrolled depression, unstable angina, uncontrolled heart failure (Class III or IV), hypotension (systolic blood pressure <100 mmHg), severe asthma or chronic obstructive pulmonary disease (COPD), symptomatic peripheral arterial disease or Raynaud's syndrome, untreated pheochromocytoma, etc.);

Refractory hypertension;

Judged by the investigator as not meeting the inclusion criteria for this study.

5.4 Withdrawal Criteria

If a subject withdraws from the study for any reason, the reason must be documented, including but not limited to the following:

Subject withdraws informed consent;

Sponsor terminates the study;

Serious adverse events affecting the subject's continued participation;

Serious protocol violation/deviation;

Poor compliance;

Lost to follow-up;

The investigator and/or sponsor believes the subject's medical condition may endanger their safety or continuing the study may harm the subject's health;

Death;

Others, such as disease progression, study indicator increase or decrease reaching the study treatment withdrawal criteria;

Others.

5.5 Termination Criteria

Trial termination criteria (the trial will be terminated if any of the following conditions are met):

Serious safety issues occur during the trial;

Major flaws are found in the clinical trial protocol during the trial;

The drug registration applicant requests termination of the trial;

The Ethics Committee requests termination of the trial;

The regulatory authority requests termination of the trial.

6. Study Medications

6.1 Investigational Medicinal Product:

Name: Metoprolol Succinate Extended-Release Tablets (Brand Name: Betaloc® ZOK)

Description: White or off-white film-coated tablets.

Dosage Form: Extended-release tablet

Specification: 47.5 mg/tablet

Route of Administration: Oral

Storage: Store below 30°C at room temperature.

Manufacturer: AstraZeneca Pharmaceutical Co., Ltd.

Packaging and Labeling Description: The investigational product will be dispensed in the original commercial packaging. All study medications will be managed centrally by the institutional pharmacy and will be affixed with a study-specific label containing information such as project number, subject number, drug code, specification, dosage and administration, storage conditions, and expiry date to ensure traceability.

6.2 Non-Investigational Drugs: Immunotherapy and Chemotherapy Drugs

6.3 Administration Method

Dosage and Administration: Subjects in the experimental group will start taking metoprolol succinate extended-release tablets 47.5 mg (one tablet) once daily, starting from Day 1 of the first cycle of preoperative neoadjuvant immunotherapy, and continue until the day before surgery. Route of administration: oral.

6.4 Dose Adjustment or Suspension Criteria:

6.4.1 Suspension Criteria: Resting heart rate persistently <50 beats/min, or systolic blood pressure persistently <90 mmHg / diastolic blood pressure <60 mmHg; occurrence of symptomatic hypotension/bradycardia such as dizziness, blackouts, fatigue, chest tightness; ECG indicates second-degree or higher atrioventricular block.

6.4.2 Dose Adjustment Criteria: If symptoms resolve and heart rate recovers to ≥55 beats/min, blood pressure recovers to ≥90/60 mmHg after temporary suspension, the original dose (47.5 mg/day) can be resumed. If the above occurs again after resuming, the dose is reduced to half (23.75 mg/day) for continued treatment.

6.4.3 Permanent Discontinuation Criteria: Recurrent hypotension/bradycardia persists despite half-dose treatment; occurrence of serious adverse reactions (e.g., cardiogenic shock, severe atrioventricular block); electrolyte imbalance (hyperkalemia >5.5 mmol/L) that cannot be corrected.

6.5 Concomitant Medications: None.

6.6 Drug Labeling and Storage: Study drugs will be affixed with a study-specific label by the central pharmacy to ensure accurate and complete information, complying with GCP standards. Study drugs will be stored in a dedicated, lockable, temperature-controlled cabinet within the clinical trial center pharmacy, managed by a study pharmacist, ensuring ambient temperature below 30°C, with regular temperature and humidity monitoring and recording.

6.7 Management and Dispensing: A central pharmacy management model will be used. After the investigator issues an electronic study prescription, the subject will collect the medication from the central pharmacy. The study pharmacist will dispense the medication according to the randomization results (if applicable) and complete detailed dispensing and return records.

6.8 Drug Return and Destruction: During each visit, the investigator or study nurse will verify the quantity of medication dispensed during the previous visit and collect any remaining medication and empty packaging. Returned drugs (including unused and used packaging) will be counted and recorded by the study pharmacist and temporarily stored in a designated area. After the study is completed and the data management department confirms database lock, all remaining study drugs will be uniformly registered and destroyed following institutional standard operating procedures and relevant regulations; destruction records will be retained.

7. Study Methods and Procedures

All subjects must sign the informed consent form before screening. Subjects who pass screening can enter the study. Subjects will be treated according to the protocol. Efficacy and safety will be evaluated during cycles 1, 2, 3, 4, 6, 9, and 12. A telephone follow-up will be conducted 1 month after enrollment for statistical analysis. Treatment will continue until the subject enters the follow-up period or meets any withdrawal criteria. If the investigator assesses that continuing the investigational drug treatment could provide clinical benefit to the subject, treatment may continue until disease progression, intolerance, or death.

7.1 Screening Period:

All subjects need to complete screening-related assessments before enrollment, screening according to the inclusion/exclusion criteria.

Sign the informed consent form. Record demographic data: date of birth, sex, subject initials;

Record medical history and physical examination (including vital signs, height, weight, physical examination of all systems); neoadjuvant treatment regimen, start time, cycles.

Preoperative imaging stage; immunotherapy-related indicators, such as PD-L1 expression, cortisol, adrenocorticotropic hormone, tumor tissue ADRB1 expression, tumor tissue RNA sequencing, tumor immune microenvironment; preoperative gastric endoscopic biopsy immunohistochemistry: MLH1, MSH2, MSH6, PMS2, CK, EBER, Her-2, claudin 18.2, Ki67 (%).

7.2 Treatment Period:

7.2.1 Preoperative Immunotherapy Patients will receive 4 cycles of preoperative immunotherapy combined with chemotherapy (anti-PD-1 antibody + XELOX/SOX/Capoex regimen, every 3 weeks [Q3W]). All patients will take a fixed dose of metoprolol succinate extended-release tablets (47.5 mg) once daily, continuing until the day before surgery.

7.2.2 Preoperative Assessment Before undergoing surgical resection after completing neoadjuvant therapy, patients will undergo imaging assessment and immune marker tests again.

7.2.3 Postoperative Pathology Record postoperative tumor regression grade (TRG), tumor size, location, histological type, TNM stage, MLH1, MSH2, MSH6, PMS2, CK, EBER, Her-2, claudin 18.2, Ki67 (%) and other tumor-related indicators.

7.3 Follow-up Period: Patients enrolled in the study will undergo regular visits and assessments according to the specified visit schedule after surgical treatment. Follow-up is required at 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, and 36 months post-surgery. Quality of life (EORTC QLQ-C30) will also be assessed.

8. Evaluation Indicators

8.1 Effectiveness Evaluation: Postoperative pathological response rate (pathological response is defined as the proportion of patients with less than 50% viable tumor cells in the surgical specimen after neoadjuvant therapy [i.e., TRG grade 0-2 according to AJCC 8th edition criteria [20, 21]]; pathological non-response refers to patients with more than 50% viable tumor cells [i.e., TRG grade 3 according to AJCC 8th edition criteria [20, 21]]). TRG can be assessed within 1 week post-surgery; treatment compliance (immunotherapy completion rate, surgery delay rate); 3-year disease-free survival (DFS), 3-year overall survival (OS).

8.2 Safety Evaluation: Incidence and severity of adverse events.

8.2.1 Definition of Adverse Event Indicators

Bradycardia: Heart rate <60 beats/min, and a decrease of ≥10 beats/min from baseline.

Hypotension: Systolic blood pressure <90 mmHg or diastolic blood pressure <60 mmHg, or a decrease of ≥20 mmHg from baseline accompanied by clinical symptoms.

Neutropenia: Absolute neutrophil count (ANC) <2.0×10⁹/L.

Thrombocytopenia: Platelet count <100×10⁹/L.

Hand-Foot Syndrome: Numbness, paresthesia, tingling, erythema, or marked swelling on palms and/or soles, potentially progressing to desquamation, ulceration, or blistering.

8.2.2 Adverse Event Period: From signing the informed consent form (first use of study drug [beta-blocker]) to 30 days after the last dose.

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