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.

Inclusion Criteria:

1. Voluntarily agrees to participate in the study, is able to provide written informed consent, and is willing to comply with study procedures and visit schedules.

2. Age ≥ 18 years at the time of consent; sex unrestricted.

3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

4. Histologically confirmed bladder urothelial carcinoma with clinical lymph node involvement (cT1-T4a, N1-N3, M0) based on the AJCC 8th edition. Mixed histology is permitted if the urothelial carcinoma component is ≥ 50%.

5. No antihypertensive medication used during screening, with resting systolic blood pressure between 110-140 mmHg measured under natural conditions.

6. Adequate organ function as demonstrated by laboratory results obtained within 14 days prior to enrollment:

   a. No administration of hematopoietic growth factors within 14 days prior to sample collection.

   i. Absolute neutrophil count ≥ 1.5 × 10⁹/L ii. Platelet count ≥ 90 × 10⁹/L iii. Hemoglobin ≥ 90 g/L b. INR or aPTT ≤ 1.5 × ULN c. Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN in patients with Gilbert syndrome or indirect hyperbilirubinemia) d. AST, ALT, and alkaline phosphatase ≤ 2.5 × ULN e. Preoperative pulmonary function assessment indicating tolerance of major abdominal surgery.

7. Cisplatin-eligible patients, or cisplatin-ineligible patients who meet at least one of the following:

   • ECOG performance status > 1 or Karnofsky 60-70%
   • Creatinine clearance < 60 mL/min
   • Grade ≥ 2 hearing loss (NCI-CTCAE v5.0)
   • Grade ≥ 2 peripheral neuropathy (NCI-CTCAE v5.0)
   • New York Heart Association (NYHA) class III or above heart failure

8. Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to enrollment and agree to use effective contraception during the study and for ≥ 120 days after the last dose. Male participants must agree to use effective contraception during the study and for ≥ 120 days after the last dose.

Exclusion Criteria:

1. Prior treatment with PD-1, PD-L1, PD-L2, CTLA-4 inhibitors, or other T-cell co-stimulatory/checkpoint agents.

2. Systemic antineoplastic therapy or immunomodulatory therapy within 28 days prior to enrollment, including interferon, interleukin-2, or TNF-based agents.

3. Prior radiotherapy for bladder cancer.

4. Prior systemic anticancer therapy except:

   1. Previous systemic chemotherapy completed ≥ 12 months before initiation of study treatment.
   2. Intravesical chemotherapy or immunotherapy completed ≥ 7 days prior to initiation of study treatment.

5. Major surgery or significant trauma within 28 days prior to enrollment (vascular access placement and TURBT excluded).

6. Receipt of live attenuated vaccines within 28 days prior to enrollment. Inactivated influenza vaccination is allowed; intranasal influenza vaccine is not permitted.

7. Active autoimmune disease requiring systemic therapy, as judged by the investigator.

8. Long-term systemic corticosteroid therapy or other immunosuppressive medications judged to interfere with study treatment.

9. Uncontrolled systemic disease that may interfere with treatment, including:

   • Clinically relevant electrolyte abnormalities
   • Hypoalbuminemia
   • Interstitial lung disease or non-infectious pneumonitis
   • Uncontrolled diabetes, hypertension, or cardiovascular disease (including unstable angina, myocardial infarction, symptomatic heart failure, or medically managed ventricular arrhythmias within 6 months).

10. Chronic hepatitis B infection with HBV DNA ≥ 500 IU/mL (2,500 copies/mL). Patients with inactive HBsAg carrier status or viral suppression (HBV DNA < 500 IU/mL) after antiviral therapy may be enrolled. HBV DNA testing is required if anti-HBc is positive.

11. Active hepatitis C infection. Patients who are HCV antibody negative, or HCV antibody positive but HCV RNA negative, are eligible.

12. History of immunodeficiency disorders (including HIV infection), congenital or acquired immune deficiency, or prior allogeneic stem cell transplantation or organ transplantation.

13. Known hypersensitivity to monoclonal antibodies, or known allergy to propranolol or other β-adrenergic receptor blockers.

14. Toxicities from previous therapies have not returned to baseline or stabilized, unless deemed not to pose a safety risk by the investigator (e.g., alopecia, neuropathy, specific laboratory abnormalities).

15. Contraindications to propranolol, including but not limited to:

    • Unstable angina
    • Decompensated heart failure
    • Symptomatic sinus bradycardia
    • Atrioventricular block
    • Severe asthma or bronchospasm

16. Current use of oral or intravenous β-blockers (e.g., atenolol, bisoprolol, carvedilol, metoprolol) that cannot be safely discontinued or transitioned. If previously used, a washout period of at least 14 days with medical reassessment is required before enrollment.