AccScience Publishing / EJMO / Online First / DOI: 10.36922/EJMO026090097
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REVIEW ARTICLE

Molecular subtype-guided precision immunotherapy with sintilimab for gastric cancer: Efficacy, heterogeneity, mechanisms, and clinical perspectives

Jinhai Fang1* ,  Xinyue Diao2 ,  Qiulin Chen2
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1 Department of Medical Oncology, Beijing No.6 Hospital, Beijing, China
2 Department of Gastrointestinal Medical Oncology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan, China
EJMO, 026090097 https://doi.org/10.36922/EJMO026090097
Received: 25 February 2026 | Revised: 5 April 2026 | Accepted: 10 April 2026 | Published online: 13 May 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

Despite the paradigm-shifting impact of immune checkpoint inhibitors in advanced gastric cancer, a significant proportion of patients exhibit primary or acquired resistance to therapy, largely driven by the disease’s profound molecular heterogeneity. This narrative review synthesizes current evidence on how The Cancer Genome Atlas–defined molecular subtypes–microsatellite instability-high (MSI-H), Epstein–Barr virus-positive (EBV+), chromosomally unstable (CIN), and genomically stable (GS)—orchestrate distinct tumor immune microenvironments that critically determine sensitivity to sintilimab, a programmed cell death protein 1 inhibitor widely adopted in China. We highlight that MSI-H and EBV+ tumors typically foster an immunologically “hot” milieu, characterized by high tumor mutational burden, abundant CD8+ T-cell infiltration, and interferon-gamma signaling, rendering them highly responsive to sintilimab monotherapy or dual checkpoint blockade. In contrast, CIN and GS subtypes often present as “cold” or immune-excluded, necessitating rational combinations with chemotherapy or anti-angiogenic agents such as apatinib. However, we also critically appraise contradictory data, noting that not all MSI-H tumors respond equally and that the “cold” versus “hot” dichotomy represents a spectrum with significant intratumoral heterogeneity. Notably, loss-of-function mutations in AT-rich interaction domain 1A serve as a pivotal link between genomic instability and immune activation, potentially enhancing sintilimab efficacy by driving single-stranded DNA accumulation, stimulating the stimulator of interferon genes pathway, and driving subsequent type I interferon production. While landmark trials such as ORIENT-16 have validated sintilimab-based regimens, challenges persist in managing organ-specific metastases and overcoming dynamic mechanisms of resistance. We propose that integrating comprehensive molecular profiling into routine clinical practice is essential for precision immunotherapy, and future efforts should focus on validating novel biomarkers and leveraging multi-omics platforms to guide individualized treatment strategies. 

Graphical abstract
Keywords
Gastric cancer
Sintilimab
Molecular subtypes
Immunotherapy
Tumor microenvironment
Precision medicine
Funding
None.
Conflict of interest
The authors declare no conflicts of interest.
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Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing
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