Senescence-related immunosuppressive gene MFAP2 orchestrates stromal-immune crosstalk and immunotherapy resistance in gastric cancer.
6 affiliations
- 1Lanxi Traditional Chinese Medicine Hospital, Jinhua, Zhejiang, 321100, China.
- 2Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, 321000, P.R. China.
- 3Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325000, P.R. China.
- 4Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, 321000, P.R. China. [email protected].
- 5Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325000, P.R. China. [email protected].
- 6Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, 321000, P.R. China. [email protected].
Abstract
Background
Gastric cancer (GC) is a leading cause of cancer-related mortality worldwide, with poor prognosis and immune checkpoint inhibitor (ICI) resistance mediated by immune escape. Senescence-related immunosuppressive genes (SRIGs) regulate the tumor microenvironment (TME); however, their hub genes and prognostic value in GC remain unclear. This study aimed to identify hub SRIGs and explore their significance.Methods
Transcriptomic, single-cell RNA sequencing, and spatial transcriptomic data of GC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. Weighted gene co-expression network analysis and Pearson correlation analysis were used to screen for SRIGs. Eight machine learning algorithms identified the hub SRIG, which was validated by RT-qPCR, immunohistochemistry, and clinical samples. Pseudotime trajectory, CellChat, and molecular docking analyses were used to explore the underlying mechanisms and potential drugs. A pan-cancer analysis was used to verify its generalizability.Results
A senescence-related immunosuppressive signature was constructed, stratifying GC into two subtypes with distinct TME and prognosis. Microfibril-associated protein 2 (MFAP2) was identified as the hub SRIG, significantly upregulated in GC, and an independent prognostic risk factor. It was specifically expressed in extracellular matrix cancer-associated fibroblasts (eCAFs), driving their differentiation and extracellular matrix (ECM) remodeling. MFAP2⁺ eCAFs promoted M2 macrophage polarization via CSF1-CSF1R and C3-C3AR1 axes, mediating immune escape and ICI resistance. AZD4547 and MK-2461 were potential targeted drugs. Pan-cancer analysis confirmed the ubiquitous oncogenic role of MFAP2.Conclusions
MFAP2 is a hub SRIG linking eCAFs, ECM remodeling, and immune escape in GC. It serves as a reliable prognostic and ICI resistance predictor and potential therapeutic target, providing a basis for precision therapy in GC.
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BibTeX
@article{hu2026senescencerelated,
title = {{Senescence-related immunosuppressive gene MFAP2 orchestrates stromal-immune crosstalk and immunotherapy resistance in gastric cancer.}},
author = {Yichan Hu and Liaoxiang Zhu and Lijun Zhou and Yichi Zhang and Shunjie Zheng and Jiani Zhu and Ziyu Xi and Zhan Yang and Yifei Hu},
journal = {BMC cancer},
year = {2026},
month = aug,
doi = {10.1186/s12885-026-16660-5},
url = {https://europepmc.org/article/MED/42972272},
note = {CC BY},
}
RIS
TY - JOUR
TI - Senescence-related immunosuppressive gene MFAP2 orchestrates stromal-immune crosstalk and immunotherapy resistance in gastric cancer.
AU - Yichan Hu
AU - Liaoxiang Zhu
AU - Lijun Zhou
AU - Yichi Zhang
AU - Shunjie Zheng
AU - Jiani Zhu
AU - Ziyu Xi
AU - Zhan Yang
AU - Yifei Hu
PY - 2026
DA - 2026/08/04
JO - BMC cancer
DO - 10.1186/s12885-026-16660-5
UR - https://europepmc.org/article/MED/42972272
AB - Background Gastric cancer (GC) is a leading cause of cancer-related mortality worldwide, with poor prognosis and immune checkpoint inhibitor (ICI) resistance mediated by immune escape. Senescence-related immunosuppressive genes (SRIGs) regulate the tumor microenvironment (TME); however, their hub genes and prognostic value in GC remain unclear. This study aimed to identify hub SRIGs and explore their significance.Methods Transcriptomic, single-cell RNA sequencing, and spatial transcriptomic data of GC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. Weighted gene co-expression network analysis and Pearson correlation analysis were used to screen for SRIGs. Eight machine learning algorithms identified the hub SRIG, which was validated by RT-qPCR, immunohistochemistry, and clinical samples. Pseudotime trajectory, CellChat, and molecular docking analyses were used to explore the underlying mechanisms and potential drugs. A pan-cancer analysis was used to verify its generalizability.Results A senescence-related immunosuppressive signature was constructed, stratifying GC into two subtypes with distinct TME and prognosis. Microfibril-associated protein 2 (MFAP2) was identified as the hub SRIG, significantly upregulated in GC, and an independent prognostic risk factor. It was specifically expressed in extracellular matrix cancer-associated fibroblasts (eCAFs), driving their differentiation and extracellular matrix (ECM) remodeling. MFAP2⁺ eCAFs promoted M2 macrophage polarization via CSF1-CSF1R and C3-C3AR1 axes, mediating immune escape and ICI resistance. AZD4547 and MK-2461 were potential targeted drugs. Pan-cancer analysis confirmed the ubiquitous oncogenic role of MFAP2.Conclusions MFAP2 is a hub SRIG linking eCAFs, ECM remodeling, and immune escape in GC. It serves as a reliable prognostic and ICI resistance predictor and potential therapeutic target, providing a basis for precision therapy in GC.
SN - 1471-2407
ER -