Background: The addition of immunotherapy (IT) to chemotherapy (CT) significantly improved survival in patients with advanced esophageal squamous cell carcinoma (ESCC). In addition, neoadjuvant IT combined with CT was shown to be effective in resectable ESCC. Chemoradiotherapy (CRT) is still the standard treatment for inoperable locally advanced ESCC. However, little is known about the role of CT plus IT in the inductive setting before CRT in unresectable locally advanced ESCC. Therefore, we conducted a single-arm, phase Ⅱ clinical trial (ImpactCRT) to evaluate the efficacy and safety of induction CT plus camrelizumab followed by CRT in patients with unresectable locally advanced ESCC. Methods: Patients with previously untreated, unresectable locally advanced ESCC were enrolled. First, patients receive two 21-day cycles of induction therapy with nab-paclitaxel (260 mg/m²), carboplatin (area under curve 5 mg/mL per min), and camrelizumab (200 mg). Then, patients received definitive CRT consisting of 2 cycles of fluorouracil (750 mg/m²/24 hours for 5 days) and cisplatin (75 mg/m² bolus day 1) repeated every 4 weeks with concurrent 50-66 Gy in 25-30 fractions. The primary endpoint was 1-year overall survival (OS). Key secondary endpoints were OS, progression-free survival (PFS), objective response rate (ORR), and safety. Results: Between July 12, 2020 and October 14, 2022, 49 eligible patients were enrolled, consisting of 41 men and 8 women with a median age of 62 years (range, 41-74 years). All 49 patients completed two cycles of induction therapy, but 3 patients withdrew from the study due to refusal of CRT, and 46 patients were included in this analysis. 44 (95.6%) patients completed planned radiotherapy and 39 (84.8%) received two cycles of full-dose concurrent CT. With a median follow-up of 19.1 months, 8 (17.4%) patients died. Forty-two patients were evaluated for efficacy, with a confirmed ORR of 97.6%. The 6-month and 1-year PFS were 93.3% and 74.2% respectively. The 1-year OS was 87.6%. Median PFS and OS were not reached. The most common grade ≥3 adverse treatment related toxicities were thrombocytopenia (23.9%), anemia (21.7%), leukopenia (17.4%), esophagitis (13.0%), AST increase (13.0%), neutropenia (10.9%), and ALT increase (8.7%). One treatment-related death was observed. Conclusions: This preliminary analysis indicated that induction CT plus camrelizumab followed by CRT had promising efficacy and favorable tolerance profile as first-line treatment for unresectable locally advanced ESCC. This study, the first prospective study for unresectable locally advanced ESCC, demonstrated the efficacy of induction CT plus IT. This combination therapy strategy should be validated in a larger trial in the future. Clinical trial information: ChiCTR2000034304.