Background: Pts with multiple or tumors with large invasion areas that are incompletely resectable through TURBT would be recommended for radical cystectomy in the clinical treatment. The KEYNOTE-057 and SWOG S1605 studies have illuminated the efficacy of immune checkpoint inhibitors monotherapy in HR-NMIBC pts, with acceptable adverse events (AEs). This trial was designed to evaluate the efficacy and safety of tislelizumab (ICI) plus nab-paclitaxel (MTI) in HR-NMIBC pts. Methods: TRUCE-02 is a single-arm phase II study testing systemic tislelizumab 200mg on days 1 plus nab-paclitaxel 200mg on days 2 every 3 weeks (Q3W) for one year for NMIBC pts with incompletely resectable tumor by TURBT. Here we report the results for all eligible patients who received at least one protocol treatment. The primary endpoint was pathological complete response (CR) rate when pts received 3 or 4 cycles of therapy. Duration of complete response (DOR), cystectomy-free survival (CFS), overall survival (OS), and progression-free survival (PFS) using Kaplan-Meier methods (KM) were secondary endpoints. Results: Between July 2020 and December 2022, 69 pts were enrolled and included in the safety analysis, and, of those, 56 pts were eligible and included in the efficacy analysis. 34 (60.7%; 95% CI 46.8%, 73.2%) out of 56 pts achieved CR condition when completing 3 or 4 treatment cycles. At 12 months, the estimated DOR after CR was 88.1% (95% CI 76.2%, 99.9%); the median DOR was not reached. At 18 months, the estimated CFS was 70.0% (95% CI 58.1%, 84.3%), OS was 90.6% (95% CI 82.9%, 99.0%), and PFS was 74.4% (95% CI 62.5%,80.0%); the median CFS, OS, and PRS were not reached. 65 (94%) of 69 pts had treatment-related adverse events (trAEs). The most common trAEs were alopecia 47(68%), fatigue 44(64%), and rash 25(36%). 8 grade 3-4 trAEs occurred in 6 (9%) pts, including adrenal insufficiency in 2 (3%), rash in 1 (1%), myalgia or arthralgia in 1 (1%), increased creatine kinase isoenzyme in 1 (1%), hepatic enzymes increase in 1 (1%), increased glutamyl transpeptidase in 1 (1%), and decreased white blood cell count in 1 (1%). No trAE-related death was reported. Conclusions: Tislelizumab with nab-paclitaxel represents a novel treatment option with a durable and clinically meaningful activity in treating HR-NMIBC. The safety profile was consistent with that of previous experience and no new safety concerns. Clinical trial information: NCT04730232.