Journal: Advanced science (Weinheim, Baden-Wurttemberg, Germany)
This prospective, single-arm phase II study evaluated neoadjuvant tislelizumab (anti–PD-1) plus SOX (S-1 and oxaliplatin) in locally advanced gastric cancer and explored tumor microenvironment correlates of response.
Key clinical findings
- • 49 patients with locally advanced gastric cancer were treated with neoadjuvant tislelizumab + SOX followed by surgery.
- • At 3-year follow-up, median progression-free survival and overall survival were not reached.
- • Estimated 3-year PFS and OS rates were 64.1% and 73.2%, respectively, indicating durable benefit in a substantial proportion of patients.
Translational / mechanistic findings
- • Single-cell RNA sequencing of 22,248 tumor cells from 7 patients identified three distinct cancer-associated fibroblast (CAF) subtypes.
- • Spatial transcriptomics on gastric cancer samples confirmed this CAF classification.
- • Inflammatory CAFs (iCAFs) were:
- • Negatively associated with immunotherapy efficacy.
- • Linked to an immunosuppressive tumor microenvironment during PD-1 blockade plus SOX.
- • Higher iCAF scores correlated with resistance to the tislelizumab + SOX regimen, and in vitro experiments supported the immunosuppressive role of iCAFs.
Clinical implications
- • Neoadjuvant tislelizumab + SOX appears to confer promising long-term outcomes in locally advanced gastric cancer.
- • CAF heterogeneity, particularly enrichment of iCAFs, may serve as a biomarker of resistance and a potential therapeutic target to improve the effectiveness of PD-1–based neoadjuvant strategies.