Clinical Efficacy of Tislelizumab Plus Gemcitabine-Nab-Paclitaxel for Borderline Resectable Pancreatic Cancer and Chemoresistance Analysis: A Prospective Pilot Study.

BACKGROUND: Neoadjuvant therapy can improve the survival outcomes of patients with borderline resectable pancreatic cancer (BRPC). However, standard neoadjuvant regimens remain lacking. This study evaluated the clinical feasibility of tislelizumab plus gemcitabine and nab-paclitaxel in the neoadjuvant setting for BRPC. PATIENTS AND METHODS: In this prospective study, patients with BRPC preoperatively received three cycles of tislelizumab plus gemcitabine and nab-paclitaxel, and continued postoperatively. The primary endpoints were R0 resection rate and treatment-related adverse events (TRAEs). Exploratory objectives were resistance to this regimen. RESULTS: Of 30 enrolled patients, 80.0% (24/30) completed neoadjuvant therapy and underwent surgical resection. R0 resection was achieved in 80.0% (24/30) of the patients and in 100.00% (24/24) of those resected. The 12-month OS and RFS rates were 87.5% (95% CI 64.3-95.8%) and 82.8% (95% CI 60-95.8%), respectively, with median RFS of 28 months (95% CI 16.9-39.1). Most TRAEs were grade I-II, with no serious events. Quantitative proteomics combined with machine learning identified NT5DC2, FAM3D, CXCL5, and TMT1B as candidate biomarkers of resistance to this neoadjuvant regimen. In paired pre- and postoperative tissues from treatment-sensitive patients, CD8+ T-cell infiltration tended to increase and CD163+ M2-like macrophages were significantly upregulated after surgery. CONCLUSIONS: Neoadjuvant tislelizumab plus gemcitabine and nab-paclitaxel is promising for improving the resection rate in BRPC, with a favorable safety profile. NT5DC2, FAM3D, CXCL5, and TMT1B may serve as candidate biomarkers of preoperative drug resistance, and tumor immune microenvironment (TIME) analysis further reveals immune microenvironment remodeling in postoperative tumors from treatment-sensitive patients. These findings warrant validation in larger-scale studies. Trial Registration Chinese Clinical Trial registry (ChiCTR2200063680).