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This study aimed to evaluate the safety and efficacy of neoadjuvant tislelizumab combined with chemoradiotherapy in patients with resectable esophageal squamous cell cancer. It also investigates the changes in immune markers after treatment. This is an open-label, single-arm, single-institution phase 2 clinical trial. A total of 21 patients with newly diagnosed resectable esophageal cancer (cT1-2N+ / cT3-4aN0-3 M0) received 2 cycles of tislelizumab (200mg every 3 weeks for 2 cycles) concurrent with chemoradiotherapy. Radical esophagectomy was conducted within 4-6 weeks after neoadjuvant therapy. Baseline and pre-surgery PET/CT scans were performed to assess treatment response. Primary endpoints included pathological response rate (pCR) and major pathological response rate (MPR), the secondary endpoints were disease free survival and safety. Exploratory endpoints include molecular imaging research and immunological markers alterations in tumor microenvironment and circulating to further explore the factors affecting the efficacy of neoadjuvant therapy for esophageal cancer. A total of 21 patients were enrolled, and all received neoadjuvant tislelizumab combined with chemoradiotherapy, with 19 patients underwent radical esophagectomy. One patient underwent radical chemoradiotherapy due to lymph node metastases after neoadjuvant therapy. One patient died of pneumonia before surgery. Among 19 patients who underwent surgery, R0 was 100% (19/19),10 achieved pCR (52.6%), and 14 achieved MPR (73.7%). Most of treatment-related adverse event (TRAE) were grade 1-2. Grade ≥3 TRAEs included 1 anemia, 1 leukopenia, 1 neutropenia, 1 liver damage, 1 thrombocytopenia, and 1 elevated cardiac troponin T. A significant reduction in SUVmax of tumor was observed in both pCR and no-pCR patients after treatment. And SUVmax in no-pCR patients tended to be higher than pCR patients. Following neoadjuvant treatment, a significant increase of CD4+ T cells, CD8+ T cells, and memory T cells was observed within the TME. Patients with pCR had significant increase in the infiltration of CD4+ T cells, CD8+ T cells, and CD4+ Tm cells in tumor area. And significant increase in circulating CD4+ T cells, CD4+ effector memory T cells, and M1 macrophages was found after treatment. Moreover, a notably higher presence of CD4+ Tem cells and DC cells is observed in patients achieving pCR. Neoadjuvant tislelizumab combined with chemoradiotherapy for locally advanced ESCC has promising efficacy and good safety and enhances tumor immune infiltration and immunologic memory. [ABSTRACT FROM AUTHOR]