Clinical and immune correlates of response to neoadjuvant chemoimmunotherapy in dMMR/MSI-H gastric cancer

Background: Neoadjuvant chemoimmunotherapy (NCIT) has shown promising efficacy in resectable deficient DNA mismatch repair/microsatellite instability-high (dMMR/MSI-H) gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC), yet predictive biomarkers of response remain unclear. Methods: 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 (TME) features were characterized by imaging, histopathology, multi-omics profiling, and multiplex immunohistochemistry. Patients were classified as responders or non-responders based on radiological and pathological evaluations. Results: Radiological partial response was achieved in 10 of 22 patients (45.5%). Seventeen underwent R0 resection, with Becker tumor regression grades 1a, 1b, and 2 in 10, 1, and 6 cases, yielding a pathological complete response rate of 58.8%. Two-year event-free and overall survival were 81.8% and 80.7%. Non-responders exhibited poorer survival and greater baseline intratumor heterogeneity, with enriched mutations in NF1 , KDR , CDKN2A , and PLK1 . Transcriptomic profiling revealed upregulation of GYLTL1B , PHLDA1 , IGFN1 , and SH2D5 in responders, alongside activation of proliferative (E2F, MYC targets) and immune-stimulatory (TNFA-NFKB, interferon) pathways. In contrast, non-responders lacked these signatures and showed immunosuppressive TME features, including elevated methylated tumor-infiltrating lymphocytes, Th17 signature expression, and M1 macrophage infiltration. Post-treatment analysis indicated favorable immune remodeling in responders, marked by increased dendritic and NK cells and decreased M1 macrophages, while non-responders maintained an M1-dominant state. Predictive biomarkers such as CDKN2A mutation, Fanconi anemia pathway alteration, and specific transcriptomic signatures correlated with both response and prognosis. Conclusions: NCIT yielded high pathological response and survival rates in dMMR/MSI-H GAC/GEJAC. Integrated molecular and immune profiling identified genomic and transcriptomic determinants of response, supporting biomarker-guided therapeutic strategies in this molecularly defined cohort.