Three-Year Follow-Up of Neoadjuvant Tislelizumab with Chemotherapy in Locally Advanced Gastric and Gastroesophageal Junction Adenocarcinoma: Revealing Cancer-Associated Fibroblast Heterogeneity Corresponding to PD-1 Blockade Efficacy.

The potential for immunotherapy in patients with locally advanced gastric cancer (LAGC) is recently confirmed. To report the 3-year follow-up data are aimed from a novel clinical trial. This is a prospective single-arm phase II trial. Patients with LAGC received neoadjuvant tislelizumab plus SOX before surgery. Biopsies are obtained before treatment, and tumor samples post-treatment underwent single-cell RNA sequencing (scRNA-seq). Spatial transcriptomics is conducted for validation. Cox regression models and Kaplan-Meier analysis are applied. A total of 49 patients are enrolled, and the median progression-free (PFS) and overall survival (OS) are not achieved. The 3-year PFS and OS rates are 64.1% and 73.2%, respectively. scRNA-seq of 22, 248 cells from tumors from seven patients with LAGC enabled annotation of three cancer-associated fibroblast (CAF) phenotypes. Spatial transcriptomics of gastric cancer samples validate the classification, showing inflammatory CAFs (iCAFs) negatively correlated with immunotherapy efficacy. Patients with LAGC show a favorable prognosis after neoadjuvant tislelizumab plus SOX treatment. CAF heterogeneity is crucial for patients with gastric cancer undergoing immunotherapy, and iCAFs is associated with an immunosuppressive microenvironment during PD-1 blockade with SOX therapy and validated by in vitro experiments. Patients with LAGC with higher iCAF scores are resistant to SOX PD-1 blockade.