Tumor-associated macrophages in gastric cancer: Phenotypic plasticity and therapeutic targets

Abstract

Tumor-associated macrophages (TAMs) are abundant, functionally plastic cells within the gastric cancer tumor microenvironment and influence tumor growth, invasion, metastasis, angiogenesis, immune evasion, chemoresistance, and metabolic reprogramming. The M1/M2 dichotomy incompletely describes TAM states; single-cell and spatial transcriptomic studies have identified specialized populations that vary with tumor subtype, anatomical niche, and disease stage. This review synthesizes current evidence on TAM origin, recruitment, adaptation, and roles in malignant progression, and examines TAM-directed therapeutic strategies. TAM composition and polarization, rather than total macrophage density, may be more relevant to treatment response. Although TAM-targeting approaches show promise in preclinical models, direct clinical targeting in gastric cancer remains limited. Defining subtype-specific TAM states, clarifying microbiota-TAM interactions, and developing predictive biomarkers may advance precision immunotherapy.

Keywords: Gastric cancer; Tumor-associated macrophages; Tumor microenvironment; Macrophage plasticity; Single-cell transcriptomics; Immunotherapy

Core Tip: Tumor-associated macrophages (TAMs) are highly plastic immune cells that shape gastric cancer progression and treatment response. This review moves beyond the M1/M2 model by summarizing single-cell-defined TAM heterogeneity, interactions with the gastric microenvironment and microbiota, and current targeting approaches. TAM-directed strategies are predominantly preclinical; translation will require subtype-aware biomarkers and rational combination with established therapies.