Urinary Tumor DNA-Guided Systemic Immunotherapy for Unresectable Very-High-Risk Non-Muscle-Invasive Bladder Cancer

Inclusion Criteria: 1. Age ≥18 years. 2. Histologically confirmed non-muscle-invasive urothelial carcinoma of the bladder classified as very-high-risk (VHR) according to EAU 2025 guideline criteria. 3. Disease considered unresectable by the investigator and multidisciplinary team, defined as complete tumor eradication by standard transurethral resection of bladder tumor (TURBT) being not feasible or unlikely to achieve adequate local control. 4. Patients who are ineligible or refuse for radical cystectomy, after discussion with the treating team. 5. At least one measurable or evaluable bladder lesion/documented residual disease suitable for response assessment by cystoscopy, TURBT/biopsy, pathology, urine cytology, and urinary tumor DNA (utDNA) testing. 6. ECOG performance status 0-2. 7. Adequate organ function, including: Hematologic function: Absolute neutrophil count ≥1.5 × 10⁹/L, Platelet count ≥100 × 10⁹/L, Hemoglobin ≥9 g/dL Hepatic function: Total bilirubin ≤1.5 × ULN, AST ≤2.5 × ULN, ALT ≤2.5 × ULN Renal function: Serum creatinine ≤1.5 × ULN or Creatinine clearance ≥60 mL/min. 8. Ability to provide urine samples for utDNA testing and urine cytology during treatment and follow-up. Exclusion Criteria: 1. Muscle-invasive bladder cancer (≥T2), locally advanced unresectable invasive disease beyond NMIBC, or metastatic urothelial carcinoma at baseline. 2. Histology showing predominant or pure non-urothelial carcinoma of the bladder that, in the investigator's judgment, would make the patient unsuitable for this protocol. 3. Prior treatment with immune. 4. Active autoimmune disease or history of autoimmune disease requiring systemic immunosuppressive treatment and considered incompatible with immune checkpoint inhibitor therapy. 5. Ongoing systemic immunosuppressive therapy exceeding protocol-allowed doses. 7\. Active uncontrolled infection, including uncontrolled urinary tract infection, that would interfere with study treatment or response assessment. 8\. Any medical condition that would preclude safe administration of systemic immunotherapy or protocol-required cystoscopy/TURBT/biopsy, in the investigator's judgment. 9\. Concurrent other malignancy. 10. Pregnant or breastfeeding women. 11. Inability to comply with protocol procedures or follow-up.