Background: Trimodal therapy (TMT) has achieved long-term survival and persistent oncologic control in selected MIBC patients, however, tailored treatment using biomarkers based on chemotherapy plus PD-1 inhibitor responses is currently absent. Furthermore, the safety and efficacy of hypo-fractionated radiation in combination with PD-1 inhibitors and concurrent chemotherapy is worth exploring. Methods: This is a two-stage, single-arm, phase II trial recruiting cT2-4aN0-1M0 MIBC pts. Based on results of cystoscopy, urine cytology, imaging and MRD detection after first stage (Tislelizumab (T) 200 mg on D1, Cisplatin (C) 70 mg/m² on D1 and Gemcitabine (G) 1000 mg/m² on D1 and D8 Q3W for 3-4 cycles), pts achieving cCR (cT0, cTa) are treated with T, while the other pts receive T and chemoradiotherapy (whole bladder 44Gy/16 fractionation combined with C as radiosensitizer). 1-year BIDFS rate is the primary endpoint. Secondary endpoints include 2-year MFS rate, 2-year BIDFS rate and safety. Tissue and urine samples will be obtained for genetic profiling and biomarker research. Results: The preliminary efficacy and safety are reported this time. As of September 20, 2023 (median follow up: 258 (49-415) days, 25 pts with a median age of 64 (36-77) years were enrolled and 96% are male. 19 pts with cT2 (57.14%), cT3 (33.33%) and cT4 (9.52%) tumors were evaluable. 2 pts were assessed as N1. 14/19 pts (73.68%) achieved cCR and maintained a sustained response. Based on positive urine cytology and MRD, 5 pts were classified as non-cCR (2 pts in cT3N0M0, 2 pts in cT4N0M0 and 1 pt in cT2N0M0). Due to RC (2 pts achieving ypT0N0 and 1 pt achieving ypT2N0) and incomplete treatment cycles, 6 pts were excluded from the efficacy analysis set. BFS rate at 1 yr is evaluated in 6 pts (2 pts received hypo-fractionated on the second stage) and the rate is 100%. TRAEs were found in 19 of 25 pts (76%). The grade 3-4 TRAEs observed (8%) was adrenal cortical insufficiency and immuno-therapy related colonitis. Hematological AEs (32%), renal insufficiency (24%), pruritus (20%), and fatigue (20%) are the most common AEs. During hypo-fractionated radiation, no new safety signs were discovered. Conclusions: The preliminary findings indicate a potential efficacy and manageable toxicity during the two-stage treatment. Enrollment is still ongoing, and long-term efficacy will be proved. Clinical trial information: NCT05531123.