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Clinical Studies

Smad4 loss identifies aggressive subtype with immunotherapy and anti-HER-2 treatment resistance in gastric cancer

British Journal of Cancer (2025)Cite this article

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Abstract

Background

SMAD4 mutation and homozygous deletion represent the most prevalent genomic events driving aggressive biological behavior in gastric cancer (GC). However, clinical outcome and therapeutic response in GC patients with Smad4-loss remains obscure.

Methods

This study included 990 GC patients from four independent clinical centers including the Zhongshan Hospital (ZSHS) cohort, the Cancer Genomic Atlas (TCGA) cohort, the Samsung Medical Center (SMC) cohort and the Memorial Sloan Kettering Cancer Center (MSKCC) cohort.

Results

In ZSHS cohort, 60/454 GC patients harbored Smad4-loss are characterized by lower pN stage, well histology differentiation, lower EBV infection, null p53 staining and lower tumor proliferation. Smad4-loss GC patients exhibit miserable overall survival across ZSHS cohort and TCGA cohort. Moreover, Smad4-loss GC patients yield no impact on adjuvant chemotherapy, poor outcome upon anti-PD-1 immunotherapy or anti-HER-2 therapy. Interestingly, Smad4-loss GC show more well and intermediate differentiation and lower Ki67 staining. Furthermore, Smad4-loss GC exhibit tumor immunosuppressive contexture characterized with enriched CXCL13+CD8+T cells, reduced IFN-γ+ cells and GZMB+ cells infiltration.

Conclusions

Smad4 loss yields poor clinical outcome, immunotherapy and anti-HER-2 treatment resistance and tumor immunosuppressive contexture in GC patients. Our findings provide clues for further detailed biological investigation and aggressive clinical management in Smad4-loss GC patients.

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Fig. 1: Poor prognosis in Smad4-loss gastric cancer patients.
Fig. 2: Unfavorable response upon anti-PD-1 immunotherapy or anti-HER-2 therapies in SMAD4-loss gastric cancer patients.
Fig. 3: Well differentiation and low proliferation features of Smad4-loss gastric cancer.
Fig. 4: CXCL13+CD8+ T cell-enriched immunosuppressive microenvironment of Smad4-loss gastric cancer.

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Data availability

Data and materials generated that are relevant to the results are included in this article. Other data are available from the corresponding author Prof. Xu upon reasonable request.

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Acknowledgements

We would like to thank Dr. Lingli Chen (Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China) and Dr. Yunyi Kong (Department of Pathology, Shanghai Cancer Center, Fudan University, Shanghai, China) for their excellent pathological technology help.

Funding

This study was funded by grants from National Natural Science Foundation of China (82103313, 82203201, 82272786, 82303966, 82373417), China Postdoctoral Science Foundation (2023M742327), Shanghai Municipal Natural Science Foundation (23ZR1409900), Shanghai Sailing Program (21YF1407600) and Natural Science Foundation of Fujian Province (2023J05294). All these study sponsors have no roles in the study design, in the collection, analysis and interpretation of data.

Author information

Author notes

  1. These authors contributed equally: Mengyao Sun, Yun Gu, Jieti Wang.

Authors and Affiliations

  1. NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Mengyao Sun, Yun Gu, Ziqiu Zhang, Zhen Ling & Jiejie Xu

  2. Department of Gastrointestinal Surgery, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Yun Gu

  3. Department of Endoscopy, Fudan University Shanghai Cancer Center, Shanghai, China

    Jieti Wang

  4. Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Fei Shao

  5. Department of Emergency Surgery, Zhongshan Hospital, Fudan University, Shanghai, China

    Chao Lin, Hongyong He & Ruochen Li

  6. Department of Gastrointestinal Surgery, Zhongshan Hospital, Fudan University, Shanghai, China

    Hao Liu

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Contributions

MS, YG and JW for the acquisition of data, interpretation of data, statistical analysis, and drafting of the manuscript; ZZ, ZL, FS, CL and HH for technical and material support; RL, HL and JX for study concept and design, analysis and interpretation of data, drafting of the manuscript, obtained funding, and study supervision. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ruochen Li, Hao Liu or Jiejie Xu.

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The authors declare no competing interests.

Ethics approval and consent to participate

The study was approved by the Clinical Research Ethics Committee of Zhongshan Hospital, Fudan University, with the approval number Y2015-054. Written informed consent was obtained from each patient included and this study was performed in accordance with the Declaration of Helsinki.

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Sun, M., Gu, Y., Wang, J. et al. Smad4 loss identifies aggressive subtype with immunotherapy and anti-HER-2 treatment resistance in gastric cancer. Br J Cancer (2025). https://doi.org/10.1038/s41416-025-03002-8

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