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Macrophages are innate immune cells that play key roles during both homeostasis and disease. Depending on the microenvironmental cues sensed in different tissues, macrophages are known to acquire specific phenotypes and exhibit unique features that, ultimately, orchestrate tissue homeostasis, defense, and repair. Within the tumor microenvironment, macrophages are referred to as tumor‐associated macrophages (TAMs) and constitute a heterogeneous population. Like their tissue resident counterpart, TAMs are plastic and can switch function and phenotype according to the niche‐derived stimuli sensed. While changes in TAM phenotype are known to be accompanied by adaptive alterations in their cell metabolism, it is reported that metabolic reprogramming of macrophages can dictate their activation state and function. In line with these observations, recent research efforts have been focused on defining the metabolic traits of TAM subsets in different tumor malignancies and understanding their role in cancer progression and metastasis formation. This knowledge will pave the way to novel therapeutic strategies tailored to cancer subtype‐specific metabolic landscapes. This review outlines the metabolic characteristics of distinct TAM subsets and their implications in tumorigenesis across multiple cancer types. Tumor‐associated macrophages (TAMs) constitute up to 50% of the tumor mass, representing a heterogeneous population of tissue‐resident and monocyte‐derived macrophages. TAM phenotype not only involves alterations in cell metabolism but also metabolic reprogramming that can dictate their activation state and function. This review elucidates the diverse roles and metabolic traits of distinct TAM subsets in pancreatic, breast, lung and ovarian malignancies.

Large peritoneal macrophages (LPMs) are long‐lived, tissue‐resident macrophages, formed during embryonic life, developmentally and functionally confined to the peritoneal cavity. LPMs provide the first line of defense against life‐threatening pathologies of the peritoneal cavity, such as abdominal sepsis, peritoneal metastatic tumor growth, or peritoneal injuries caused by trauma, or abdominal surgery. Apart from their primary phagocytic function, reminiscent of primitive defense mechanisms sustained by coelomocytes in the coelomic cavity of invertebrates, LPMs fulfill an essential homeostatic function by achieving an efficient clearance of apoptotic, that is crucial for the maintenance of self‐tolerance. Research performed over the last few years, in mice, has unveiled the mechanisms by which LPMs fulfill a crucial role in repairing peritoneal injuries and controlling microbial and parasitic infections, reflecting that the GATA6‐driven LPM transcriptional program can be modulated by extracellular signals associated with pathological conditions. In contrast, recent experimental evidence supports that peritoneal tumors can subvert LPM metabolism and function, leading to the acquisition of a tumor‐promoting potential. The remarkable functional plasticity of LPMs can be nevertheless exploited to revert tumor‐induced LPM protumor potential, providing the basis for the development of novel immunotherapeutic approaches against peritoneal tumor metastasis based on macrophage reprogramming. Research performed over the last few years that has widened the knowledge on resident peritoneal macrophages by unveiling the mechanisms by which these cells fulfill a crucial role in repairing peritoneal injuries, form mesothelium‐bound immune aggregates to control microbial infections, and promote peritoneal metastatic tumor growth.

The explosion of new information in recent years on the origin of macrophages in the steady-state and in the context of inflammation has opened up numerous new avenues of investigation and possibilities for therapeutic intervention. In contrast to the classical model of macrophage development, it is clear that tissue-resident macrophages can develop from yolk sac-derived erythro-myeloid progenitors, fetal liver progenitors, and bone marrow-derived monocytes. Under both homeostatic conditions and in response to pathophysiological insult, the contribution of these distinct sources of macrophages varies significantly between tissues. Furthermore, while all of these populations of macrophages appear to be capable of adopting the polarized M1/M2 phenotypes, their respective contribution to inflammation, resolution of inflammation, and tissue repair remains poorly understood and is likely to be tissue- and disease-dependent. A better understanding of the ontology and polarization capacity of macrophages in homeostasis and disease will be essential for the development of novel therapies that target the inherent plasticity of macrophages in the treatment of acute and chronic inflammatory disease.

Macrophages within solid tumors and metastatic sites are heterogenous populations with different developmental origins and substantially contribute to tumor progression. A number of tumor-promoting phenotypes associated with both tumor- and metastasis-associated macrophages are similar to innate programs of embryonic-derived tissue-resident macrophages. In contrast to recruited macrophages originating from marrow precursors, tissue-resident macrophages are seeded before birth and function to coordinate tissue remodeling and maintain tissue integrity and homeostasis. Both recruited and tissue-resident macrophage populations contribute to tumor growth and metastasis and are important mediators of resistance to chemotherapy, radiation therapy, and immune checkpoint blockade. Thus, targeting various macrophage populations and their tumor-promoting phenotypes holds therapeutic promise. Here, we discuss various macrophage populations as regulators of tumor progression, immunity, and immunotherapy. We provide an overview of macrophage targeting strategies, including therapeutics designed to induce macrophage depletion, impair recruitment, and induce repolarization. We also provide a perspective on the therapeutic potential for macrophage-specific acquisition of trained immunity as an anti-cancer agent and discuss the therapeutic potential of exploiting macrophages and their traits to reduce tumor burden.

Introduction Macrophages are essential in maintaining homeostasis, combating infections, and influencing the process of various diseases, including cancer. Macrophages originate from diverse lineages: Notably, tissue‐resident macrophages (TRMs) differ from hematopoietic stem cells and circulating monocyte‐derived macrophages based on genetics, development, and function. Therefore, understanding the recruited and TRM populations is crucial for investigating disease processes. Methods By searching literature databses, we summarized recent relevant studies. Research has shown that tumor‐associated macrophages (TAMs) of distinct origins accumulate in tumor microenvironment (TME), with TRM‐derived TAMs closely resembling gene signatures of normal TRMs. Results Recent studies have revealed that TRMs play a crucial role in cancer progression. However, organ‐specific effects complicate TRM investigations. Nonetheless, the precise involvement of TRMs in tumors is unclear. This review explores the multifaceted roles of TRMs in cancer, presenting insights into their origins, proliferation, the latest research methodologies, their impact across various tumor sites, their potential and strategies as therapeutic targets, interactions with other cells within the TME, and the internal heterogeneity of TRMs. Conclusions We believe that a comprehensive understanding of the multifaceted roles of TRMs will pave the way for targeted TRM therapies in the treatment of cancer.

Macrophages are heterogeneous immune cells with diverse subtypes and tissue‐specific distributions, displaying dynamic polarization states that critically govern their immunomodulatory functions and responses to environmental cues. As key regulators of innate and adaptive immunity, they originate from either embryonic progenitors or bone marrow‐derived monocytes and exhibit remarkable plasticity in response to microenvironmental cues. Tissue‐resident macrophages (e.g., Langerhans cells, Kupffer cells, microglia) display unique organ‐specific functions, while inflammatory stimuli drive their polarization into proinflammatory (M1) or anti‐inflammatory (M2) phenotypes along a functional continuum. This review systematically examines macrophage subtypes, their anatomical distribution, and the signaling pathways (e.g., NF‐κB, STATs, PPARγ) underlying polarization shifts in acute and chronic inflammation. We highlight how polarization imbalances contribute to pathologies including neuroinflammation, liver fibrosis, and impaired tissue repair, particularly in aging contexts. Furthermore, we discuss emerging therapeutic strategies targeting macrophage plasticity, such as cytokine modulation, metabolic reprogramming, and subtype‐specific interventions. By integrating recent advances in macrophage biology, this work provides a comprehensive framework for understanding their dual roles in immune regulation and tissue homeostasis, offering insights for treating inflammatory and age‐related diseases through macrophage‐centered immunomodulation. Macrophages originate from the yolk sac, fetal liver, and bone marrow, differentiating into two main subtypes: M1‐like (proinflammatory) and M2‐like (anti‐inflammatory). These subtypes exhibit high plasticity, allowing them to transform in response to environmental cues or therapeutic interventions. In various chronic inflammatory conditions, such as aging and cancer, the polarization and functions of macrophages in various tissues (including liver, lung, kidney, skin, and brain) undergo significant alterations. They enter an imbalanced state, characterized by excessive M1‐like activation, weakened phagocytosis, aggravated inflammation, and muscle atrophy. Senescence‐associated secretory phenotype (SASP) factors further exacerbate these changes, leading to chronic inflammation and tissue dysfunction.

Bacillus Calmette‐Guérin (BCG) still remains the only licensed vaccine for TB and has been shown to provide nonspecific protection against unrelated pathogens. This has been attributed to the ability of BCG to modulate the innate immune system, known as trained innate immunity (TII). Trained innate immunity is associated with innate immune cells being in a hyperresponsive state leading to enhanced host defense against heterologous infections. Both epidemiological evidence and prospective studies demonstrate cutaneous BCG vaccine‐induced TII provides enhanced innate protection against heterologous pathogens. Regardless of the extensive progress made thus far, the effect of cutaneous BCG vaccination against heterologous respiratory bacterial infections and the underlying mechanisms still remain unknown. Here, we show that s.c. BCG vaccine‐induced TII provides enhanced heterologous innate protection against pulmonary Streptococcus pneumoniae infection. We further demonstrate that this enhanced innate protection is mediated by enhanced neutrophilia in the lung and is independent of centrally trained circulating monocytes. New insight from this study will help design novel effective vaccination strategies against unrelated respiratory bacterial pathogens. Synopsis Subcutaneous BCG vaccine‐induced trained innate immunity in the lung provides enhanced heterologous innate protection against pulmonary Streptococcus pneumoniae infection. This enhanced protection is mediated by increased neutrophilia in the lung and is independent of trained circulating monocytes. Subcutaneous BCG vaccination protects against pulmonary S. pneumoniae infection. Augmented neutrophilia in the lung of BCG‐vaccinated hosts plays a critical role in enhanced protection. Trained circulating monocytes do not contribute to enhanced heterologous protection in the lung of BCG‐vaccinated hosts. Graphical Abstract Subcutaneous BCG vaccine‐induced trained innate immunity in the lung provides enhanced heterologous innate protection against pulmonary Streptococcus pneumoniae infection. This enhanced protection is mediated by increased neutrophilia in the lung and is independent of trained circulating monocytes.

Nuclear receptors regulate key functions of mononuclear phagocytes and are critical components of the innate immune system, acting as regulators of organ health and disease. In healthy mice, the loss of the nuclear orphan receptor NR2F6 alters tissue‐resident macrophage populations in the liver, lung, and spleen. In response to Salmonella Typhimurium infection, Nr2f6‐deficient mice exhibit improved clinical outcomes, characterized by reduced weight loss, bacterial loads in the spleen and liver, and decreased plasma pro‐inflammatory cytokines. Despite unchanged basal iron metabolism in the spleen and liver, iron regulatory proteins and the interleukin (IL)‐6‐hepcidin axis are altered in Nr2f6‐deficient mice during Salmonella infection, reducing hypoferremia. Transcriptomic analysis of splenic red pulp macrophages reveals significant alterations of phagocytosis‐related genes, including upregulation of signal‐regulatory protein alpha (Sirpa). In vitro, phagocytosis of red blood cells, regulated by the inhibitory CD47‐Sirpα axis, and Salmonella Typhimurium phagocytosis are significantly impaired in Nr2f6‐deficient splenic macrophages. Blocking Sirpα in vitro restores the phagocytic activity of Nr2f6‐deficient macrophages to wild‐type levels. In vivo, Salmonella Typhimurium loads are partially increased post‐infection in anti‐Sirpα treated Nr2f6‐deficient mice. These findings uncover a previously unrecognized role of NR2F6 in host‐pathogen interactions, positioning it as a potential therapeutic target for infectious diseases. Loss of nuclear receptor NR2F6 reduces tissue‐resident macrophage populations. Nr2f6‐deficient mice are protected from weight loss and bacterial load during infection with Salmonella Typhimurium. Pro‐inflammatory cytokines and iron levels are altered in infected Nr2f6‐deficient mice. Enhanced Sirpα levels reduce phagocytic uptake in Nr2f6‐deficient splenic macrophages. Blocking Sirpα partially adjusts phagocytic responses of Nr2f6‐deficient macrophages to wild‐type.

Objective: The objective was to find out the expression of EphB4 receptor and ephrin-B1 ligand by the macrophages that live inside the mouse testicles. Materials and Methods: Messenger ribonucleic acid (mRNA) expression of EphB4 and ephrin-B1 was identified via RT-PCR amplification, and protein expression was examined by immunostaining. Results: Analysis using RT-PCR revealed that mRNA of EphB4 and ephrin-B1 were noticed in the examined testis of all postnatal ages. Furthermore, immunostaining revealed that F4/80-positive intra-testicular-resident macrophages were located in the intertubular spaces within the testis and more densely around the intra-testicular excurrent duct system, and increased in number gradually during the postnatal period of development until 5 weeks of age, when the mice attain their maturity (puberty), and maintained thereafter. Both EphB4 and ephrin-B1 immunoreactiv¬ity were noticed in F4/80-positive intra-testicular-resident macrophages within the testis of all studied postnatal ages. Ephrin-B1 and EphB4 immunoreactivity were weak during early postnatal development until the age of 2 weeks, and then ephrin-B1 immunoreactivity became very strong and EphB4 immunoreactivity became strong at the age of 3 weeks, and they continued to do so until the age of 8 weeks. Furthermore, EphB4 receptor was tyrosine-phosphorylated in testis. Conclusion: The expression of EphB4 and ephrin-B1 in mice intra-testicular-resident macro¬phages is being examined for the first time in this work. The localization of EphB4 and ephrin-B1, and EphB4 tyrosine-phosphorylation suggest that EphB4/ephrin-B1 signaling might occur in the intra-testicular-resident macrophages, and may participate in maintaining male fertility.

Resident macrophages of different organs have structural and functional features, which can complicate their identification and analysis. A promising candidate for the role of a universal immunohistochemical marker of resident macrophages is the calcium-binding protein Iba-1, a well-known marker of brain microglia. The purpose of this work was to study the possibility of using one variant of antibodies to the Iba-1 protein for the immunohistochemical detection of resident macrophages in the liver, myocardium, lung, and choroid plexus of the rat brain. The study was performed on male Wistar rats ( n = 15). It was shown that the use of rabbit monoclonal antibodies against Iba-1 allows highly effective detection of Kupffer cells in the liver, resident macrophages in the myocardium, alveolar and interstitial macrophages in the lung, and Kolmer cells in the choroid plexus of the rat brain. In all cases, the reaction is characterized by a high specificity and the absence of background staining. In contrast to the classical marker of macrophages, the CD68 molecule, the Iba-1 protein is evenly distributed in the cytoplasm of cell bodies and processes. This makes it possible to more fully identify cells using immunostaining for Iba-1, carry out their three-dimensional reconstructions, and study their structural and functional organization. Immunohistochemical reaction against Iba-1 can be successfully used as a universal alternative to other common methods for identifying resident macrophages.