Beta-Blockers on the Efficacy of Neoadjuvant Immunotherapy for Gastric Cancer

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

• 3-year overall survival (OS) [Срок оценки: From the start of study treatment (first dose of neoadjuvant immunotherapy) to death from any cause, assessed up to 36 months post-surgery. The 3-year OS rate is measured at 36 months after surgery.]
• 3-year progression-free survival (PFS) [Срок оценки: From start of study treatment to the first documented disease progression or death, assessed up to 36 months post-surgery. The 3-year PFS rate is measured at 36 months after surgery.]
• Correlation with immunotherapy-related biomarkers [Срок оценки: Pre-treatment tumor biopsy at baseline; blood samples at baseline and before surgery (approximately 4 months); post-treatment tumor tissue from surgical resection specimen (approximately 1 week after surgery).]
• Pathological response of MPR [Срок оценки: From completion of neoadjuvant therapy to surgical resection; assessed on postoperative pathological specimen approximately 1 week after surgery, up to 4 months after study treatment initiation.]