Abstract
Gastric cancer (GC) is often diagnosed at an advanced stage due to the absence of early symptoms and low screening rates, resulting in poor prognosis. The progression of GC is closely related to the immune response within the tumor microenvironment (TME). Tumor-associated macrophages (TAMs), particularly the M2 subtype, are the most prevalent inflammatory cells in the TME and play a crucial role in GC. Tumor cells also evade immune surveillance by upregulating CD274. OTUB2, a deubiquitinase, regulates tumor progression by deubiquitinating substrate proteins. However, the role of OTUB2 in TAMs polarization and immune evasion in GC remains unclear. Stable OTUB2 overexpression and knockdown cells were cocultured with M0 macrophages to study TAMs polarization. Flow cytometry was used to analyze M2 TAMs and CD274 expression on GC cells. Cytokine secretion was evaluated by ELISA. T cell killing assays were performed by co-culturing GC cells with CD8+ T cells. Co-immunoprecipitation and Western blotting assessed the ubiquitination levels of YAP, TAZ and CD274. In vivo studies were conducted to evaluate OTUB2’s effect on TAMs polarization, immune evasion and GC progression. Immunohistochemistry of GC tissues was performed to investigate the correlation between OTUB2 and TME components. OTUB2 overexpression activated YAP/TAZ to increase TGF-β1 and M2 TAMs polarization by inhibiting SMAD7. It also enhanced CD274 expression, promoting immune evasion. OTUB2 deubiquitinated YAP, TAZ, and CD274, preventing their degradation. In vivo, OTUB2 increased M2 TAMs polarization and CD274 expression, exacerbating GC progression. Immunohistochemistry confirmed a positive correlation between OTUB2, M2 TAMs infiltration and CD274 levels and a negative correlation with CD8+ T cell infiltration. Kaplan–Meier analysis showed reduced overall survival in GC patients with high OTUB2 expression. OTUB2 promotes M2 TAMs polarization and immune evasion in GC. Targeting OTUB2 offers a promising strategy to reshape the GC TME and improve the efficacy of immune checkpoint inhibitors.
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Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
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Funding
This study was funded by the Beijing Natural Science Foundation (7232117), Noncommunicable Chronic Diseases-National Science and Technology Major Project (2026ZD0553803 and 2024ZD0520602), Fundamental Research Funds for the Central Universities, Peking Union Medical College (3332025013 and 3332025120), Peking Union Medical College Hospital Research Funding for Postdoc (kyfyjj202503), Development Center for Medical Science & Technology National Health Commission of the People’s Republic of China (WKZX2024CX102214), CIMF-CSPEN Project Management Committee (Z-2017-24-2403), Bethune Charitable Foundation (STLKY2-139) and Postdoctoral Fellowship Program of China Postdoctoral Science Foundation (GZC20251393).
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JL and JS conceived the project and designed the research studies. JL, JS, CZ and YH performed most of the experiments described. YL provided help with animal and technical assistance in the experiments. ZZ and GL provided conceptual advice and helpful discussion. JL and JS analyzed the data. JL and YH prepared the manuscript. WK and XY supervised the study and contributed to polishing and reviewing the manuscript. All the authors contributed to the article and approved the submitted version.
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The study was subjected to rigorous review and approved by the Clinical Ethics Committee of PUMCH, CAMS (Approval No. K1447). In accordance with the guidelines outlined in the Declaration of Helsinki, written informed consent was acquired from each patient or their legal representative before specimen collection. The animal experiments conducted in this study were evaluated and authorized by the Animal Ethics Committee of PUMCH, CAMS (Approval No. XHDW-2022-108).
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Li, J., Sun, J., Zhang, C. et al. OTUB2 induces M2 tumor-associated macrophage polarization and increases CD274 expression in gastric cancer cells to aggravate the progression of gastric cancer. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08743-9
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DOI: https://doi.org/10.1038/s41419-026-08743-9
