Background: Long course radiotherapy plus neoadjuvant chemotherapy followed by resection (total mesorectal excision, TME) has accepted widespread recognized in the treatment of locally advanced rectal cancer (LARC). Tislelizumab, an anti-PD1 humanized IgG4 monoclonal antibody, has been demonstrated with clinical activity and is approved for treating recurrent/refractory classical Hodgkin lymphoma and locally advanced/metastatic urothelial carcinoma in China. Long course (neoadjuvant chemoradiotherapy, NCRT) plus tislelizumab followed by TME for LARC might bring better downstaging effect and reduce the risk of distant relapse. Methods: This trial was designed to evaluate the safety and efficacy of LARC patients treated with long course NCRT plus tislelizumab followed by TME. Stage II/III LARC patients (cT₃N₀M₀ and cT_1-3N_1-2M₀) with the tumor distal location ≤ 10 cm from anal verge at six centers in China were consecutively enrolled. The enrolled patients received long course radiotherapy (50 Gy/25 f, 2 Gy/f, 5 days/week) and three 21-day cycles capecitabine (1000 mg/m², bid, po, day1-14) plus three 21-day cycles tislelizumab (200 mg, iv.gtt, day8), followed by TME 6-8 weeks after the end of radiotherapy. Whether and how to use postoperative adjuvant chemotherapy will be determined according to clinical experience. The primary efficacy endpoint will be the pathological complete response (pCR) rate, which is defined as absence of viable tumor cells in primary tumor and lymph nodes. Results: From June 2021 to January 2022, a total number of patients (n = 20) were enrolled. The median age was 63 (from 32 to 76) years while the median tumor distal location was 4.9 (from 1.5 to 9.9) cm. As of Januray 31, 12 patients with non-MSI-H/pMMR LARC had undergone TME surgery, with sphincter saving resection rate and R0 resection rate of 100%. The pCR rate was 58.3 % (7/12) and objective response rate reached 100 % (12/12). Of patients without pCR, 3 (25 %) patients reached tumor regression grade 1, while 2 (16.7 %) patients reached grade 2 according to AJCC standard. The neoadjuvant rectal (NAR) score of all 12 patients was 7.18 ± 11.01 (from 0.00 to 30.07). 2 (16.7 %) immune-related adverse events (irAEs) including 1 patient with diarrhea (grade 3) and 1 with vitiligo (grade 1) were observed. Anastomotic leakage (Clavien-Dindo grade II) occurred in 1 (8.3 %) of 12 patients, while no treatment-related death occurred. Conclusions: Tislelizumab added to long course NCRT followed by TME exhibited favorable pCR rate with manageable toxicities and postoperative complication, including non-MSI-H/pMMR LARC. The preliminary results are promising, which provide a potential strategy for neoadjuvant therapy against LARC. Research Sponsor: BeiGene, Ltd. Clinical trial information: NCT04911517.