Background: Radical cystectomy (RC) was recommended to patients (pts) with HR NMIBC BCG-unresponsive papillary tumors. Clinical unmet need was to explore non-surgical treatment options for pts who were ineligible for or refused RC. Our study aimed to evaluate the efficacy and safety of tislelizumab combined with radiotherapy as bladder-preserving treatment for pts with HR NMIBC unresponsive to BCG. Methods: This open-label, single arm phase II study enrolled pts with HR NMIBC BCG-unresponsive papillary tumors (high-grade Ta or T1 tumors without carcinoma in situ). The papillary tumors should be removed all visible lesions by transurethral resection of bladder tumor (TURBT). Within 2 weeks after TURBT, eligible pts received tislelizumab 200 mg in day 1 (D1), every 21 days for eight cycles and a total radiotherapy dose of 60-66 GY in 30-33 fractions over seven weeks. The primary end point was disease-free survival (DFS) rate at 12 months (defined as no reappearance of high grade or T1 tumors or clinical stage development after the therapy). Secondary end points were bladder-preservation rate, OS and safety. Our study anticipated a DFS rate at 12 months was 45% and the study would enroll 32 pts to meet the primary endpoint. Results: By Sep. 2022, 14 eligible pts were enrolled. Ten pts have completed therapy and were analyzed (male 90.0%; median age 58 years (31-79); pure TCC 100%; median tumor size 1.0 cm (0.5-2.0); 40% multiple papillary tumours; median eGFR, 91.1 mL/(min•1.73m²) (46.1-115.5); high-grade Ta 40.0%, T1 60.0%; median of 11 previous BCG instillations (9-19)). Median follow-up was 20.3 months (9.9-28.1), the median number of tislelizumab cycles was 8 (2-8) and radiotherapy doses was 60 GY (60-66) in 30 fractions. The DFS rate at 12 month was 80.0% (95%CI, 67.4%-92.6%), at 24 month was 60.0% (95%CI, 40.3%-79.7%). Two pts showed reappearance of high-grade Ta and received TURBT, one patient showed stage development from T1N0M0 to M1 disease and received systemic treatment. The bladder-preservation rate at 24 months was 100% (95%CI, 100%-100%). The OS rate at 24 months was 100% (95%CI, 100%-100%). Treatment related adverse events (TRAEs) of any grade were rash (40.0%), neutropenia (10.0%), hyperthyroidism (10.0%), AST/ALT increased (10.0%) and hyperglycaemia (10.0%). 5 pts experienced immune related AEs, including rash (n=4, G1-2), hyperthyroidism (n=1, G2), hyperglycaemia (n=1, G3) and AST/ALT increased (n=1, G3). Conclusions: Our preliminary results supported the use of tislelizumab combined with radiotherapy as a promising bladder-preserving therapy for pts with BCG-unresponsive HR NMIBC who were ineligible for or refused RC. Clinical trial information: ChiCTR2000035275.