# 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

## TL;DR

A 3-year follow-up study shows that combining immunotherapy with chemotherapy improves outcomes for patients with advanced gastric cancer, with findings highlighting the role of specific fibroblast types in treatment response.

## Contribution

The study reveals cancer-associated fibroblast heterogeneity and its impact on PD-1 blockade efficacy in gastric cancer immunotherapy.

## Key findings

- The 3-year progression-free and overall survival rates are 64.1% and 73.2%, respectively.
- Inflammatory CAFs (iCAFs) are negatively correlated with immunotherapy efficacy.
- Higher iCAF scores are associated with resistance to PD-1 blockade in gastric cancer.

## Abstract

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.

Heterogeneous cancer‐associated fibroblasts orchestrate dual immune microenvironments in LAGC.