Background: Radical cystectomy (RC) was recommended to HR NMIBC patients (pts) with BCG-unresponsive papillary tumors. Clinical unmet need was to explore non-surgical treatment options for pts who were ineligible for or declined RC. Our study was established to evaluate the efficacy and safety of tislelizumab combined with radiotherapy as bladder-preserving treatment for HR NMIBC pts unresponsive to BCG. Methods: This open-label, single arm phase II study enrolled HR NMIBC pts with 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 64 GY in 32 fractions over seven weeks. The primary endpoint 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 endpoints were bladder-preservation rate, OS and safety. Our study estimated a DFS rate at 12 months was no less than 50% and the study would enroll 32 pts to meet the primary endpoint. Results: By Jan. 2024, 25 eligible pts were enrolled. 23 pts have completed therapy and were analyzed (male 78.2%; median age 61 years (31-80); pure TCC 100%; median tumor size 1.0 cm (0.5-2.5); high-grade Ta=52.2%, T1=47.8%; 47.8% multiple papillary tumours; median previous BCG instillations 13 (7-22)). Median follow-up was 25.8 months (6.3-41.1), the mean number of tislelizumab cycles was 7.3 and radiotherapy doses was 62.8 GY. The DFS rate at 12 month was 75% (95%CI, 46.3%-100%), at 24 month was 50% (95%CI, 12.3%-87.7%). Three pts showed reappearance of high-grade Ta and received TURBT, two pts showed reappearance of T1 and received TURBT, and one pt 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 (30.7%), radiocystitis (15.4%), neutropenia (7.7%), hyperthyroidism (7.7%), hypothyroidism (7.7%), oral ulcer (7.7%), diarrhea(7.7%), AST/ALT increased (7.7%) and hyperglycaemia (7.7%). 7 pts experienced immune related AEs, including rash (n=4, G1-2), hyperthyroidism (n=1, G2), hypothyroidism (n=1, G1), diarrhea (n=1, G1), hyperglycaemia (n=1, G3) and AST/ALT increased (n=1, G3). Conclusions: Our interim results supported the use of tislelizumab combined with radiotherapy as a promising bladder-preserving therapy for BCG-unresponsive HR NMIBC pts who were ineligible for or decline RC. Clinical trial information: ChiCTR2000035275.