Natural metabolites targeting macrophage polarization for non-small cell lung cancer therapy: A review of mechanisms and applications based on chemical classification

Abstract

Non-small cell lung cancer (NSCLC) accounts for roughly 85% of lung cancer cases and is a leading cause of cancer-related death worldwide. Reprogramming tumor-associated macrophages (TAMs) from a pro-tumor M2 phenotype to an anti-tumor M1 phenotype has emerged as a promising therapeutic strategy. This review examines naturally occurring metabolites that modulate TAM polarization in NSCLC, organized into eight chemical classes: flavonoids, alkaloids, terpenoids, polysaccharides, saponins, stilbenoids, lignans, and phenolic acids. A recurring finding is that these compounds converge on shared signaling pathways, particularly PI3K/Akt/mTOR, NF-κB, and STAT family members, while each class also displays distinct mechanistic tendencies. Flavonoids couple redox modulation with immune effects. Alkaloids engage multiple targets but carry dose-dependent toxicity. Terpenoids show strong tumor microenvironment penetration and synergy with immune checkpoint inhibitors. Polysaccharides act through membrane receptors such as Toll-like receptors and Dectin-1. Saponins largely center on AMPK signaling. The remaining classes, though supported by fewer studies, point to MDSC regulation and context-dependent effects. Multi-component plant extracts and traditional Chinese medicine formulas also influence TAM polarization and have reached adjuvant clinical use. Delivery platforms such as nanoparticles, hydrogels, and exosomes are being developed to address poor bioavailability. Translation remains limited by a lack of trials with TAM-specific endpoints, an oversimplified M1/M2 framework, and the need for standardized pharmacokinetic and targeting assessments. Future progress will require biopsy-based TAM phenotyping, biomarker-driven patient stratification, and delivery systems matched to metabolite properties.