Neoadjuvant tislelizumab with chemoradiotherapy for resectable locally advanced esophageal squamous cell carcinoma

BACKGROUND: Combining neoadjuvant immunotherapy with chemoradiotherapy may improve outcomes in esophageal cancer; however, factors underlying its effectiveness remain unclear. This study evaluated the efficacy of neoadjuvant tislelizumab combined with chemoradiotherapy and investigated changes in immunological indicators to identify individuals who may benefit from neoadjuvant treatment. METHODS: This open-label, single-arm, single-institution phase II trial included 21 patients with newly diagnosed resectable esophageal cancer who received tislelizumab with chemoradiotherapy. Nineteen patients underwent radical esophagectomy within 4-6 weeks of neoadjuvant therapy. Baseline and preoperative positron emission tomography/computed tomography scans were performed to assess treatment response. The primary endpoints were pathological complete response (pCR) and major pathological response (MPR) rate; secondary endpoints were disease-free survival (DFS) and safety. Exploratory endpoints included changes in the tumor microenvironment and circulating immunological markers following neoadjuvant treatment and factors influencing treatment efficacy. RESULTS: Among 19 patients, 10 achieved pCR (52.6%), and 14 achieved MPR (73.7%). The 3-year DFS and overall survival rates were 65.2% and 95.2%, respectively. The treatment was generally well-tolerated, with most adverse events being grades 1-2; however, one treatment-related death from pneumonia occurred prior to surgery. Neoadjuvant tislelizumab treatment combined with chemoradiotherapy significantly increased CD4 +, CD8 +, and memory T cell counts within the tumor and stromal regions. Patients with pCR exhibited significantly increased CD4 +, CD8 +, and CD4 + Tm cell infiltration in the tumor area and CD8 + and CD8 + Tm cell infiltration in the tumor stroma. Tm cells in the tumor and stromal regions at baseline and following treatment were associated with improved DFS. Furthermore, a pre-existing, suppressive peripheral immune profile was strongly associated with disease progression. CONCLUSION: Neoadjuvant tislelizumab with chemoradiotherapy shows promising efficacy and a manageable safety profile in esophageal squamous cell carcinoma, with key immunological signatures, such as memory T cell responses, emerging as strong predictors of long-term clinical benefit.