4075 Background: This study aimed to evaluate the efficacy and safety of PD-1 combined with chemotherapy as neoadjuvant therapy in patients with locally advanced EC and sought to explore biomarkers related to treatment prognosis and efficacy prediction for screening patients who would benefit most from this therapy. Methods: In this phase 2 study, patients (pts) with histopathologically confirmed ESCC, diagnosed as clinical stage cT1-3N1-3M0 and ECOG PS 0-1 were enrolled to receive two cycles of neoadjuvant chemoimmunotherapy with PD-1 blockade (Pembrolizumab/Tislelizumab on d1) plus nab-paclitaxel (260mg/m2 in total on d1 and d8) and cisplatin (60mg/m2 in total on d1-3) of each 21-day cycle, followed by esophagectomy. Biopsied pretreatment tumor tissues along with surgical tumor specimens were collected for RNA sequencing. The primary endpoint was complete pathologic response (pCR) rate. The secondary endpoints were overall response rate (ORR), event-free survival (EFS), overall survival (OS) and safety. Biomarkers associated with clinical prognosis were assessed as exploratory objectives. Results: From Jan 11, 2021 to, Apr 25 2022, 56 pts were enrolled and 42 pts received neoadjuvant therapy and operation. Among them, 66.7% (28/42) had clinical complete response, 50% (21/42) had partial response, and ORR was 78.6% (33/42). 42 pts underwent surgical resection, achieving a 100% (42/42) R0 resection rate and a pCR rate of 33.3% (14/42), tumor regression grade (TRG, Mandard system) 1, 2 and 3 were 14.3% (6/42), 14.3% (6/42) and 71.4% (30/42) respectively. With a median follow-up of 24.4 months (range 14.3-33.4), 12(28.6%) patients had disease recurrence. Within 24 months, 14.3% (2/14) pts who achieved pCR experienced recurrence. 2-year EFS rate was 54.8% (95%CI,43.4, 66.3% ), 2-year OS rate was 81.5% (95%CI,69.4, 90.2% ). Overall, grade ≥3 AEs included leukopenia (11.9% [5/42]), thrombocytopenia (4.8% [2/42]), and no deaths were due to TRAEs. With 34 patients of RNA sequenced, we divided the patients into two groups based on whether they had recurred within 24 months as favorable prognosis and poor prognosis respectively, to analyze gene expression in different treatment effect. The poor outcome patients had significant molecular differences were seen in PI3K−Akt pathway gene expression, markers of immune activation, and genes involved in ECM−receptor interaction and focal adhesion in baseline samples, and the pathway enriched by differential genes expression in samples after treatment validated this result. Conclusions: Combining PD-1 blockade with nab-paclitaxel and cisplatin is feasible and effective in patients with locally advanced resectable ESCC, and might be a promising approach for neoadjuvant treatment. Clinical trial information: NCT05028231 .