Macrophages in immunoregulation and therapeutics Original paper

What was reviewed?

This review examined how macrophages regulate immune responses across health and disease, with a strong focus on activation, polarization, metabolic control, and signaling pathways. The authors synthesized evidence on classical M1 and alternative M2 macrophage states, describing how cytokines, pattern-recognition receptors, metabolic intermediates, and mechanical cues shape macrophage behavior. The paper also reviewed macrophage roles in infection control, inflammation, tissue repair, cancer progression, and therapeutic resistance. It integrated signaling pathways such as NF-κB, STATs, IRFs, and metabolic regulators, including glycolysis, the TCA cycle, NADPH production, and reactive oxygen species. The review aimed to clarify how macrophage plasticity drives immune balance and how dysregulation contributes to chronic inflammation, autoimmunity, and tumorigenesis.

Who was reviewed?

The authors reviewed data from human studies, murine models, and in-vitro macrophage systems derived from bone marrow, peripheral blood monocytes, and tissue-resident macrophages. The review covered macrophages across multiple organs, including lung, liver, gut, skin, brain, and tumor microenvironments. It also incorporated findings from disease models involving bacterial infection, cancer, autoimmune disorders, and metabolic disease. Rather than focusing on a single population, the paper integrated evidence across experimental systems to describe conserved and context-specific macrophage behaviors.

Most important findings

The review showed that macrophage function depends on tightly regulated polarization and metabolic programming. Pro-inflammatory M1 macrophages rely on aerobic glycolysis, pentose phosphate pathway activity, and NADPH-driven production of nitric oxide and reactive oxygen species to kill pathogens. Anti-inflammatory M2 macrophages favor oxidative phosphorylation, fatty-acid oxidation, and arginine metabolism to support tissue repair and immune suppression. The authors emphasized that metabolites such as succinate, citrate, itaconate, and glutathione actively signal to control cytokine output and transcriptional programs. The review also highlighted macrophage interactions with microbes, noting that bacterial products activate pattern-recognition receptors to drive inflammatory signaling, while some microbial species can alter macrophage autophagy and antimicrobial capacity. These findings position macrophage metabolic and redox states as measurable immune signatures relevant to host–microbe interactions and disease progression.

Key implications

This review reinforces macrophages as central regulators of immune balance rather than passive effector cells. For clinicians, it highlights that targeting macrophage metabolism, polarization, or redox signaling may improve outcomes in infection, cancer, and inflammatory disease. The findings support therapeutic strategies that reprogram macrophages instead of broadly suppressing immunity, with implications for immunotherapy response, infection control, and chronic inflammatory conditions.