BackgroundEsophageal cancer is one of the most common malignant tumors, with China accounting for 50% of the world's total incidence. Concurrent chemoradiotherapy (cCRT) with platin-based dual-drug regimen is the standard treatment for inoperable, locally advanced esophageal cancer in patients with a good performance status. However, certain patients possess risk factors that heighten toxicity and reduce their tolerance to cCRT, thereby challenging the feasibility of standard treatment. This study evaluates an alternative therapeutic approach combining programmed cell death protein 1 inhibitor (PD-1 inhibitor), definitive radiotherapy, and immunonutrition support for patients with unresectable non-metastatic esophageal cancer expressing PD-L1 who are intolerant to cCRT.MethodsThis is a phase II, single-arm, multicenter clinical trial involving patients with histologically confirmed unresectable esophageal squamous cell carcinoma (ESCC), who exhibit positive PD-L1 and are unsuitable for cCRT. Participants will receive a total radiotherapy dose of 50-60 Gy in 25-30 fractions, sintilimab (200 mg every three weeks), alongside, supplemented by enteral nutritional emulsion (600-1600 ml/day). The primary endpoint is the 1-year progression-free survival rate, with secondary endpoints including objective response rate, overall survival and incidence of adverse events.ConclusionThis research has the potential to redefine treatment for inoperable ESCC patients who cannot tolerate conventional therapies. By evaluating a less toxic regimen that combines immunotherapy, radiotherapy, and nutritional support, we aim to determine if this approach can improve both survival rates and quality of life. The synergistic effects of immunonutrition support and PD-1 inhibitor will also be explored.Trial registrationNCT06342167.