Metabolic reprogramming, ferroptosis, and tumor-associated macrophage states: mechanistic crosstalk and therapeutic prospects

Abstract

Tumor metabolic reprogramming serves as a fundamental driver of malignancy, fueling cancer cell growth while reshaping the immune landscape through metabolite accumulation. Ferroptosis, an iron-dependent form of regulated cell death, is intricately linked to these metabolic shifts. In the tumor microenvironment, tumor-associated macrophages (TAMs) are pivotal in modulating immune evasion and therapeutic resistance through diverse and context-dependent functional states. Emerging evidence suggests that metabolic alterations can dictate TAM functional plasticity by intersecting with ferroptosis-related pathways. However, the precisely orchestrated mechanisms within the “tumor metabolism-ferroptosis-TAM” axis remain to be fully integrated. This narrative review critically examines current evidence on tumor metabolic reprogramming and its impact on ferroptosis and TAM functional-state remodeling. We specifically focus on the molecular crosstalk through which metabolic and ferroptosis-associated signals may shape macrophage inflammatory, immunoregulatory, tissue-remodeling, and oxidative-stress-associated programs, and discuss potential combinatorial strategies targeting this regulatory axis.

Keywords

Ferroptosis / tumor metabolic reprogramming / tumor-associated macrophages / macrophage polarization / tumor microenvironment / immunotherapy

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