Journal Article

CAF-macrophage crosstalk in tumour microenvironments governs the response to immune checkpoint blockade in gastric cancer peritoneal metastases

Zheng, Yashang, Liang, Cheng-Cai, Liu, Ze-Xian, Yuan, Shuqiang, Xu, Rui-Hua, Wei, Wei, Zhao, Bai-Wei, Pan, Yi-Qian, Xu, Yuhong, Zuo, Zhijun, Chen, Junquan, Zeng, Zhao-Lei, Yu, Kai, Li, Yuanfang, Luo, Hui-Yan, Huang, Jiaqian, Zheng, Yongqiang, Zhang, Qihua, Nie, Run-Cong, Wu, Qi-Nian

2025

Overview

BackgroundPeritoneal metastasis is the most common metastasis pattern of gastric cancer. Patients with gastric cancer peritoneal metastasis (GCPM) have a poor prognosis and respond poorly to conventional treatments. Recently, immune checkpoint blockade (ICB) has demonstrated favourable efficacy in the treatment of GCPM. Stratification of best responders and elucidation of resistance mechanisms of ICB therapies are highly important and remain major clinical challenges.DesignWe performed a phase II trial involving patients with GCPM treated with ICB (sintilimab) combined with chemotherapy. The samples of primary tumours, GCPMs and peripheral blood from patients were collected for single-cell sequencing to comprehensively interpret the tumour microenvironment of GCPM and its impacts on immunotherapy efficacy.ResultsThe GCPM ecosystem coordinates a unique immunosuppressive pattern distinct from that of primary GC, which is dominated by a stroma-myeloid niche composed of SPP1+tumour-associated macrophages (TAMs) and Thrombospondin 2 (THBS2)+matrix cancer-associated fibroblasts (mCAFs). Consequently, this stroma-myeloid crosstalk is the major mediator of ICB resistance in patients with GCPM. Mechanistically, the accumulated THBS2+mCAFs facilitate the recruitment of peritoneum-specific tissue-resident macrophages and their transformation into SPP1+TAMs via the complement C3 and its receptor C3a receptor 1 (C3AR1), thereby forming a protumoral stroma-myeloid niche. Blocking the C3-C3AR1 axis disrupts the stroma-myeloid crosstalk and thereby significantly improves the benefits of ICB in in vivo models.ConclusionOur findings provide a new molecular portrait of cell compositions associated with ICB resistance in patients with GCPM and aid in the prioritisation of therapeutic candidates to potentiate immunotherapy.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Animals / Cancer / Cancer therapies / Cancer-Associated Fibroblasts - metabolism / Cell culture / Cells / Chemotherapy / complement / Complement component C3 / Complement component C3a / Complement receptors / Cytotoxicity / drug resistance / Female / Fibroblasts / Gastric cancer / Genomes / Humans / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / Immunotherapy / Lymphocytes / Macrophages / Male / Metastases / Metastasis / Mice / Molecular modelling / Neutrophils / Original Research / Patients / Peripheral blood / Peritoneal Neoplasms - drug therapy / Peritoneal Neoplasms - immunology / Peritoneal Neoplasms - secondary / Peritoneum / Plasma / Single-Cell Analysis / Stomach / Stomach Neoplasms - drug therapy / Stomach Neoplasms - immunology / Stomach Neoplasms - pathology / Stroma / Thrombospondin / Tumor microenvironment / Tumor Microenvironment - immunology / Tumor-Associated Macrophages - immunology / Tumor-Associated Macrophages - metabolism / Tumors