Backgr ound: Patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) suffer a high risk of distant metastasis and require guideline-recommended multimodality therapy. However, cisplatin-based concurrent chemotherapy leads to a high incidence of severe toxicities and low patient compliance, consequently limiting survival improvement. Toripalimab, an immune checkpoint inhibitor targeting programmed cell death 1 (PD-1), has a novel anti-cancer mechanism and mild toxicity spectrum. Robust evidence showed that given toripalimab + gemcitabine-cisplatin (GP) chemotherapy regimen, the median progression-free survival could be markedly improved in patients with recurrent and metastatic NPC. Besides, PD-1 antibody + radiotherapy is also regarded as a promising therapeutic strategy due to the synergistic effect. Therefore, we hypothesized that the de-intensification strategy using toripalimab + induction chemotherapy (IC) followed by radiotherapy alone would obtain equivalent survival and low toxicity in patients with LA-NPC compared with toripalimab + IC followed by concurrent chemoradiotherapy. Methods: TheTIRA study is a multicenter, randomized, controlled, open-label, phase III study. Since August 2021, we have been recruiting high-risk LA-NPC patients (stage III-IVa, except T_3-4N₀M₀& T₃N₁M₀) from 12 Chinese centers. Our target sample size is temporarily set at 494 patients with 247 for each arm. Patients will be 1:1 ratio randomized to the experimental or control arm. Patients in the experimental arm will receive induction-concurrent toripalimab (240 mg, d1, Q3W × 6 cycle) with IC (gemcitabine 1000 mg/m², d1 & d8 + cisplatin 80 mg/m², d1, Q3W × 3 cycle) + intensity-modulated radiotherapy (IMRT, 70 Gy in 33 fractions), and thereafter adjuvant toripalimab (240 mg, d1, Q3W × 11 cycle). Patients in the controlled arm will receive an additional concurrent cisplatin (100 mg/m², d1, Q3W × 2 cycle). The primary endpoint is the 3-year failure-free survival. Secondary endpoints include 3-year overall survival, 3-year distant metastasis-free survival, 3-year locoregional recurrence-free survival, quality-of-life assessment according to the systems of the European Organization for Research and Treatment of Cancer and the Functional Assessment of Cancer Therapy, and safety profile. Exploratory analysis will be performed for potential biomarkers of survival prediction including PD-L1 expression and tumor-infiltrating lymphocytes. Clinical trial information: NCT04907370.