Frontiers in Macrophage Research: From Microenvironment Regulation to Novel Strategies for Disease Treatment

As versatile guardians of the immune system, macrophages not only phagocytose invaders but also serve as vital regulators of tissue homeostasis. As central components of the innate immune system, macrophages have long been regarded as basic "scavengers". Recent studies, however, have revealed their remarkable plasticity and diversity, with involvement in nearly all physiological and pathological processes. These cells exert dual functions: they phagocytose pathogens and cellular debris, while also playing crucial roles in tissue development, homeostatic maintenance, tissue repair, and immune regulation. With the advancement of emerging technologies, research on macrophages has entered a new era, uncovering unprecedented complexity in their cellular functions.

I. Microenvironment and Macrophage Heterogeneity
The functions of macrophages are highly dependent on their microenvironment. Macrophages in different tissues exhibit distinct surface antigen profiles and receptor characteristics; even within the same tissue, they show substantial phenotypic variation. Studies have demonstrated that peritoneal macrophages from mice receiving intraperitoneal lipopolysaccharide (LPS) injections exhibit marked differences in morphology and bactericidal phagocytic capacity compared to their in vitro LPS-treated counterparts. This directly demonstrates the profound influence of the microenvironment on macrophage phenotypes.

A recent groundbreaking study has identified a novel macrophage subpopulation (LPAM) that is specifically enriched in the hepatic sinusoids. These cells delay the progression of non-alcoholic steatohepatitis (NASH) by suppressing neutrophil infiltration and contribute to the maintenance of sympathetic nervous system structural integrity. This discovery highlights the close relationship between macrophages' spatial distribution and their specialized functions.

II. New Techniques and Methods in Macrophage Research
1. Mechanical Phenotyping Decoding Based on Atomic Force Microscope and Deep Learning
The Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, has developed a novel method that combines atomic force microscopy (AFM) with deep learning to analyze the mechanical phenotypes of human macrophages in a label-free and non-invasive manner. This technique captures morphological and nanomechanical properties—including Young's modulus, adhesion force, and sphericity—at the single-cell level across different activation states. Using deep neural networks, this method enables the dynamic classification of macrophages into their M0, M1, and M2 functional phenotypes. This breakthrough overcomes technical limitations in traditional immune phenotype identification, providing a novel tool for immune monitoring and inflammatory disease diagnosis.

2. Combination of 3D Mesoscopic Imaging and Single-Cell Sequencing
By integrating whole liver imaging with single-cell RNA sequencing, researchers can precisely map the spatial distribution of specific macrophage subpopulations within tissues and analyze their functional characteristics. This multidimensional approach provides a powerful tool for understanding the functions of spatially localized immune cells, significantly advancing our comprehension of macrophage heterogeneity.

Table 1: Comparison of Novel Techniques in Macrophage Research
 

Technical Method	Resolution	Advantages	Application Scenarios
Atomic force microscope + deep learning	Nano scale	Non-marking, non-invasive, real-time monitoring	Mechanomyofunctional phenotype identification and polarization status recognition of macrophages
3D mesoscopic imaging + single-cell sequencing	Single-cell level	Spatial positioning + transcriptional information combination	Discovery and functional analysis of new subgroups of macrophages in tissues
Living imaging techniques	Cellular level	Real-time observation of cell interactions	Tracing the interaction between mast cells and macrophages

III. Metabolic Adaptation of Macrophages
A collaborative study by the French National Center for Scientific Research (CNRS) and the University of Colorado has revealed a remarkable metabolic capacity of macrophages: these immune cells can directly convert phagocytosed bacteria into nutrients for their own metabolism. Surprisingly, macrophages extract nutrients from dead bacteria more efficiently than from live bacteria. This difference may arise from an intrinsic regulatory mechanism that inhibits nutrient acquisition from live bacteria during phagocytosis. This protective mechanism could prevent the intake of potentially harmful components or excessive inflammatory responses.

The findings not only shed light on macrophages' survival strategies in an infected environment but also open new avenues for tackling antibiotic resistance and developing new vaccines or antibiotics.

IV. Interaction Between Macrophages and Other Immune Cells
1. Cross-Cell Regulation of Macrophages and Mast Cells
The latest study has found that after being phagocytosed by macrophages, mast cells can significantly enhance the multifunctional activity of macrophages and induce atypical polarization—characterized by both classical activation (M1) and alternative activation (M2) features—via granule secretion.

This granulocyte-mediated "intercellular inclusion transfer" mechanism endows macrophages with enhanced environmental adaptability and multifunctionality. The observation of the same phenomenon in psoriasis lesions provides translational medical evidence for developing therapeutic strategies targeting the MC-Mph axis.

2. Application of hiPSC-Derived Macrophages in Anti-Tumor Immunity
A research team at Zhejiang University of Technology has developed a method to differentiate human induced pluripotent stem cells (hiPSCs) into macrophages (hiPS-Mφ), addressing the issue of limited sources of conventional macrophages.

Research has demonstrated that co-culturing hiPS-Mφ with lung cancer cells significantly reduces cell viability and induces apoptosis. As the proportion of hiPS-Mφ increases, the inhibitory effect on lung cancer cells becomes more pronounced, while simultaneously altering the tumor microenvironment from an immunosuppressive state to a pro-inflammatory environment. This study provides new insights for applying macrophages in therapeutic strategies targeting lung cancer and other malignancies.

Table 2: Effects of Co-Cultivation of hiPS-Mφ and Lung Cancer Cells (Reference)
 

hiPS-Mφ:Lung Cancer Cell Ratio	H1975 Cell Apoptosis Rate	PC-9 Cell Apoptosis Rate	TNF-α Secretion Changes
1:5	14.2±2.11%	15.4±0.65%	H1975: decreased first, then increased; PC-9: significantly increased
1:1	22.1±0.45%	29.9±0.67%	Ditto
5:1	33.9±0.59%	48.5±0.21%	Ditto

 

 

Figure: The Dual Role of Macrophages: Both Anti-Tumor and Pro-Tumor Effects [1]

V. Future Directions of Macrophage Research
With the continuous advancement of research technologies, macrophage research is evolving toward a more refined, dynamic, and personalized direction. Future research priorities may include the following:
1. The association between macrophage energy metabolism and immune function: investigating how macrophages regulate metabolic pathways in response to different environments, and how metabolic reprogramming influences their immune function;
2. Clinical significance of macrophage heterogeneity: exploring the specific role of different macrophage subgroups in specific diseases and their potential as diagnostic markers or therapeutic targets;
3. Macrophage-engineered therapeutic strategies: developing cell-based therapies based on macrophages for the treatment of cancer, autoimmune diseases, and infectious diseases using gene editing and cell reprogramming technologies;
4. Neuroimmune interaction: conducting in-depth studies on the bidirectional communication mechanism between macrophages and the nervous system, especially its significance in inflammatory and neurodegenerative diseases.

Macrophage research has transcended the traditional "scavenging" concept, evolving into highly specialized, adaptable, and multifunctional immune regulators. With emerging technologies, our understanding of macrophages' complexity continues to deepen, opening new therapeutic avenues for various diseases. For researchers, this marks a golden age of macrophage biology exploration, where every new discovery could unlock critical insights into disease mechanisms.

The future of macrophage research lies in understanding how they communicate with their environment. As recent studies reveal, novel subpopulations of macrophages in the hepatic sinusoids not only regulate inflammation but also play a crucial role in neuroprotective mechanisms. This cross-system interaction is fundamentally reshaping our understanding of the immune system.

Reference Documentation
[1] Macrophage Polarity and Disease Control. DOI: 10.3390/ijms23010144

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