Immune niche composed of C1Q+ macrophages/SFRP2+ CAFs/CD8+ T cells drives immunotherapy response in HER2-positive gastric cancer

Abstract

Human epidermal growth factor receptor 2 (HER2) expression is a distinctive feature of a subgroup of gastric cancer (GC) but the underpinning characteristics of the immune microenvironment and mechanisms remain unclear. In the study, spatial transcriptomics and single-cell RNA sequencing are used on treatment-naïve HER2-positive and HER2-negative GC specimens to characterize the tumor microenvironment and spatial architecture with the aim of defining how HER2 status shapes the tumor immune microenvironment (TIME) and its cellular interactions. We find that C1Q⁺ macrophages spatially and functionally interact with CD8⁺ T cells via Galectin-9 (LGALS9), which is downregulated in HER2-positive tumors. Knocking down LGALS9 enhancesCD8⁺ T cell function and suppresses tumor growth in a CD8⁺ T cell-dependent manner, further amplified by anti-PD-1 treatment. Conversely, SFRP2⁺ cancer-associated fibroblasts (CAF) promote CD8⁺ T cell exhaustion through CXCL12-CXCR4 signaling, and knocking down CXCL12 reverses this immunosuppressive effect. HER2-positive tumors are characterized by an immune-favorable niche enriched in C1Q⁺ macrophages and CD8⁺ T effector memory cells but a decrease in SFRP2⁺ CAFs, suggesting its potential as a predictive biomarker for response to combined anti-PD-1 and anti-HER2 therapies. These findings provide insight into the spatial and immune landscape of HER2-associated GC and may inform future precision treatment strategies. HER2-positive gastric cancers represent a distinct subtype of the disease showing favourable response to combination therapy involving HER2 targeting and immune checkpoint blockade immunotherapy. Here the authors show by spatial transcriptomics and single-cell RNA sequencing that HER2 positivity associates with a favourable immune microenvironment that also determines their better response to immunotherapy.