Mitochondrial regulation of tumor-associated macrophage function

Abstract

Tumor-associated macrophages (TAMs) adapt to hypoxia, nutrient competition, lipid accumulation, and anticancer treatment. Mitochondria contribute to this adaptation through energy metabolism, redox signaling, mitochondrial DNA (mtDNA) sensing, and metabolite-dependent regulation of gene expression. This Review examines mitochondrial dynamics, mitophagy, proteostasis, respiratory remodeling, and lipid-droplet interactions, distinguishing direct TAM evidence from findings in other experimental systems. Tumor studies link these processes to IL-12 and IL-10 production, interferon responses, antigen presentation, and lymphocyte recruitment, with effects that vary by pathway and macrophage state. These findings do not establish a single optimal level of mitochondrial quality control. We discuss how macrophage lineage, spatial niche, and treatment exposure may influence the response to mitochondrial interventions. Therapeutic development will require causal validation in defined TAM populations, selective delivery, and measurements of immune function alongside mitochondrial changes. Evidence in human TAMs and direct studies of organelle contacts remain limited. Somatic mtDNA variation is considered separately from altered gene expression and DNA release, with lineage-tracing evidence distinguished from functional causation.