scRNA‐Seq in Gastric Cancer Reveals Macrophage‐Derived C1q as a Diagnostic Marker

Abstract

ABSTRACT Tumor‐associated macrophages (TAMs) and the complement system play pivotal roles in reshaping the chronic inflammatory microenvironment and driving malignant transformation. Although C1QA+ TAMs have been identified in multiple tumor types, their role in gastric cancer (GC) remains unexplored. Single‐cell RNA sequencing (scRNA‐seq) was performed on paired tumor tissues and adjacent tissues from three treatment‐naïve patients to map macrophage heterogeneities. To evaluate the clinical and translational value of C1q, immunohistochemistry (IHC) was conducted on 100 GC samples, and C1q concentrations were measured via ELISA in plasma from a multi‐center cohort of 240 patients and 100 GC tissue. Additionally, the effects of C1q‐mediated THP‐1‐derived macrophages on the malignant behaviors of GC cells were investigated using in vitro migration. Transcriptomic analysis of 56,151 single cells successfully identified a distinct pro‐inflammatory subset: C1QA+ TAMs. IHC staining demonstrated that C1q and CD163 were highly co‐expressed in compromised tissues, and their elevated expression significantly correlated with poor patient prognosis. Multi‐center plasma analysis revealed that elevated circulating C1q levels robustly enhanced clinical diagnostic accuracy. In vitro functional assays confirmed that C1q significantly primed M2 macrophage polarization, thereby accelerating the migration of GC cells. We first identified and functionally validated the C1QA+ TAM subset as a key driver of microenvironmental remodeling. C1q serves as a crucial mediator of macrophage polarization and holds strong promise as a novel, non‐invasive biomarker for the early diagnosis.