This is a prospective, multicenter, Phase Ib clinical study designed to evaluate the safety and preliminary efficacy of propranolol combined with tislelizumab plus gemcitabine/cisplatin (GC) as neoadjuvant therapy for patients with bladder urothelial carcinoma with clinical lymph node involvement (cT1-T4aN1-3M0). Current neoadjuvant immunochemotherapy regimens can improve clinical outcomes in cisplatin-eligible patients; however, patients with lymph node metastasis show a significantly poorer pathological complete response (pCR) rate compared with non-metastatic cases. Real-world clinical observations have shown that more than 20% of patients achieve complete response in the primary tumor after immunotherapy but have persistent or progressive positive lymph nodes, suggesting unique resistance mechanisms within lymph node metastatic lesions. Preclinical studies conducted by our team demonstrated that sympathetic innervation within lymph nodes releases norepinephrine, which activates β-adrenergic signaling in metastatic tumor cells and promotes lipid metabolic reprogramming, leading to CD8⁺ T-cell exhaustion and immune resistance. Propranolol, a non-selective β-adrenergic blocker, may reduce metabolic stress and restore antitumor immunity, potentially enhancing the efficacy of immune checkpoint blockade. In this study, enrolled patients will receive oral propranolol in combination with intravenous tislelizumab and standard GC chemotherapy prior to surgery. Participants will be closely monitored for treatment-related adverse events, including cardiovascular events, hematologic toxicity, and immune-related reactions. The primary endpoint is dose-limiting toxicity (DLT). Secondary endpoints include pathological complete response (pCR), pathological downstaging, safety, and survival outcomes. Exploratory analyses will evaluate changes in immune cell populations in tumor tissues, lymph nodes, and peripheral blood. The results of this study aim to provide evidence for new neoadjuvant strategies targeting lymph node metastatic bladder cancer and support the development of personalized therapeutic approaches.
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Incidence of Dose-Limiting Toxicities (DLTs)
Timeframe: At the end of Cycle 1 (each cycle is 28 days)