Qiao Tang,1,2,* Liang Tang,1,2,* Xiaofeng Wang,1,* Yongxin Zhang,1 Wenwei Liu,3 Ting Yang,3 Yuxin Wu,1 Yuanchen Ma,3 Tianxiang Lei,4 Wu Song1 

1Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-SenYou University, Guangzhou, Guangdong, People’s Republic of China; 2Laboratory of Surgery, The First Affiliated Hospital, Sun Yat-SenYou University, Guangzhou, Guangdong, People’s Republic of China; 3Center for Stem Cell Biology and Tissue Engineering, Sun Yat-SenYou University, Guangzhou, Guangdong, People’s Republic of China; 4Department of Thyroid and Hernia Surgery, Guangdong Provincial People’s Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Tianxiang Lei; Email leitianxiang@gdph.org.cn Wu Song, Email songwu@mail.sysu.edu.cn

Purpose: The peritoneum is a common site of metastasis in gastric cancer (GC), associated with poor prognosis and significant morbidity. The proclivity of GCs to metastasize to the peritoneum has been hypothesized to occur due the latter’s immunosuppressive microenvironment, such as stromal infiltration and M2 macrophage enrichment, which are associated with increased risk of PM. As far as we know, a model that can effectively predict the prognosis of patients with GCPM is still lacking. Consequently, we constructed a prognostic risk model based on M2 macrophages associated with gastric cancer peritoneal metastasis, aiming to enhance predictive precision and guide tailored therapeutic interventions.
Methods: M2 macrophage-associated genes were identified in combination with marker genes from single-cell RNA sequencing (scRNA-seq) and modular genes from weighted gene coexpression network analysis (WGCNA). A prognostic model was constructed via LASSO analysis and validated in internal and external cohorts. We further compared the immune microenvironment, immune checkpoints, and chemotherapeutic drug sensitivity between patient groups stratified by risk to clarify the immune landscape in the GCPM.
Results: Our study identified 38 M2 macrophage-related genes via single-cell and bulk RNA sequencing. We developed a prognostic model based on the expression levels of 4 signature genes: DAB2, SPARC, PLTP, and FOLR2. The feasibility of the model was validated with internal and external validation sets (TCGA, GSE62254 and IMvigor210). The model also supported the prediction results of prognosis on the basis of the immunohistochemical results. Notably, patients with higher risk scores had a lower proportion of MSI-H and TMB, a higher prevalence of stages III–IV, and a lower likelihood of responding favorably to immunotherapy.
Conclusion: Our prognostic risk model could effectively predict the prognosis and response to chemo-immune therapy in patients with GCPM. The risk score is a promising independent prognostic factor that is closely correlated with the immune microenvironment and clinicopathological characteristics.

Keywords: gastric cancer, peritoneal metastasis, scRNA-seq, M2 macrophages, immunotherapy response, prognosis