Molecular and immune determinants of response in locally advanced deficient DNA mismatch repair/microsatellite instability-high gastric or gastroesophageal junction adenocarcinoma treated with neoadjuvant chemoimmunotherapy

Neoadjuvant chemoimmunotherapy (NCIT) shows promise for resectable deficient DNA mismatch repair/microsatellite instability-high (dMMR/MSI-H) gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC). However, biomarkers associated with treatment response remain inadequately defined. We analyzed 22 patients with resectable dMMR/MSI-H GAC/GEJAC treated with perioperative sintilimab plus oxaliplatin and S-1 (SOX). Clinical response, pathological regression, genomic alterations, and tumor microenvironment characteristics were assessed using imaging, histopathology, multi-omics, and multiplex immunohistochemistry. Of the 22 patients, radiological partial response was observed in 10, yielding an objective response rate of 45.5%. Seventeen patients underwent surgery, all achieving R0 resection. Becker tumor regression grades 1a, 1b, and 2 were observed in 10, 1, and 6 patients, respectively, corresponding to a pathological complete response rate of 58.8% (10/17). Two-year event-free and overall survival rates were 81.8% and 80.7%, respectively. Non-responders demonstrated worse survival and higher baseline intratumor heterogeneity, with enriched mutations in NF1, KDR, CDKN2A, and PLK1. Transcriptomic analysis revealed significant upregulation of GYLTL1B, PHLDA1, IGFN1, and SH2D5 in responders, along with activation of proliferative (E2F, MYC targets) and immune-stimulatory (TNFA via NFKB, IFN responses) pathways. Conversely, non-responders lacked these transcriptional signatures and displayed immunosuppressive features, including elevated methylated tumor-infiltrating lymphocytes (MeTIL) and T helper 17 (Th17) signature expression and increased infiltration of M1 macrophages. Post-treatment analysis showed favorable immune remodeling in responders, characterized by reduced M1 macrophages and increased dendritic and NK cell populations. Non-responders, however, exhibited minimal immune shifts but persistent M1 macrophage elevation. Certain biomarkers, including CDKN2A mutations, Fanconi anemia pathway alterations, and specific transcriptomic signatures, were found to correlate with both treatment response and prognosis. NCIT achieved high response rates and favorable survival outcomes in dMMR/MSI-H GAC/GEJAC. These findings underscore the potential of molecular-guided risk stratification to better predict treatment responses and personalized therapeutic strategies in this patient population.