Background: Platinum-based chemotherapy is standard of care after radical nephroureterectomy for patients with high risk UTUC. However, more than half of UTUC patients may suffer from severe renal function loss which limits the use of cisplatin. Here we report the efficacy and safety results of T in the neoadjuvant treatment of patients with high risk UTUC who are ineligible for cisplatin-based chemotherapy. Methods: Eligible patients had high risk UTUC defined as pathological high-grade UTUC (either by endoscopic biopsy or urinary cytology) and/or invasive aspect on radiological examination(cT2-T4a N0/X M0) and/or hydronephrosis, ECOG PS 0-2, no prior systemic therapy and ineligible for cisplatin. Patients with variant histology on biopsy were included. Patients were given T 200mg IV every 3 weeks for at most 4 cycles followed by surgery (radical nephroureterectomy or ureteral resection or endoscopic ablation). CTU or contrast enhanced MRI examination was performed before the third dose and another before the surgery. The primary endpoint was pCR(pT0N0). The secondary endpoint included PaR(＜pT2N0) and safety. Results: 16 patients were recruited between Mar 2021 and Sep 2022: median age was 65 years(46-71), 13(81.3%) male, 14(87.5%) cT3-cT4, 4(25%) cN+. All patients received at least 2 doses of T but 7 patients didn't accept all 4 doses as planned. 9 patients received radical nephroureterectomy, 1 patient received endoscopic ablation, 3 patients received segmental ureteral resection. 3 patients declined surgery due to disease progression or adverse events. Best radiological tumor response before surgery were 6(37.5%) cPR, 7(43.8%) cSD and 3(18.7%) cPD. Overall, 4 patients achieved pCR(25%) after surgery, among which 3 patients received radical nephroureterectomy. 1 patient received endoscopic ablation with no residual disease observed in specimens and was assessed as pCR after surgery with no recurrence observed 1 year after surgery. 7 patients were evaluated as ＜pT2N0. Grade 3/4 TRAE was 18.8%. No new safety signals were observed. Conclusions: The trial demonstrated a promising pCR rate of neoadjuvant tislelizumab in patients with high risk UTUC who were ineligible for cisplatin-based chemotherapy. Further exploratory analysis is ongoing to investigate underlying correlation between tumor immune microenvironment and treatment response. Clinical trial information: NCT04672330.