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The Role of Macrophages in Cancers
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The Role of Macrophages in Cancers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 20 October 2025 | Viewed by 3291

Special Issue Editor

Dr. Pierre Tennstedt

E-Mail Website
Guest Editor
Martini-Klinik at Medical University Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany
Interests: prostate cancer; diagnosis; oncology; statistic; R project for statistical computing; biomarker
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A large proportion of tumors consist of non-malignant cells that influence the tumor microenvironment (TME). These include tissue-resident cells and a large proportion of recruited immune cells. In the early stages of tumorigenesis, these immune cells, which include activated T cells and macrophages, are recruited to eradicate the abnormal cells. Macrophages can elicit a robust anti-tumoral response via direct tumor cell elimination, and an adaptive immune response by presenting tumor antigens and secreting cytokines and chemokines that lead to recruitment of cytotoxic CD8+ T cells and natural killer (NK) cells. If eradication is not achieved, the tumor progress and the TME is modified to support the tumor and promote its progression, while the immune system is suppressed. Tumor-associated macrophages (TAM) differentiate and polarize from monocytes or tissue-resident macrophage progenitors recruited from the blood or surrounding tissue. They support tumor progression directly via the release of cytokines and or chemokines. The C-C motif chemokine ligand 2 (CCL2) and the colony-stimulating factor 1 (CSF-1) play an important role in recruitment; interleukins 4/10/13, interferon-gamma (IFN) and the tumor necrosis factor alpha (TNF) for macrophage function and polarization; and vascular endothelial growth factor A (VEGFA) and the angiogenic CXC chemokines CXCL8/12 in the process of vascularization. TAMs can also support the invasion of tumor cells, which detach from the primary tumor, spread through the blood and lymphatic system, and form micro-metastases. For that, TAMs secrete epidermal growth factor ligands and produce cathepsins and matrix metalloproteinases (e.g., MMP9), which improve tumor cell invasive properties. The process of metastasis is closely linked to the WNT signaling pathway, and so the secretion of wingless-related integration site 7b (WNT7B) by TAMs may be a key factor. Under the influence of the TME, the function of the TAMs is altered to support immunosuppression and suppress NK cell and T cell activation and function. For this purpose, they form inhibitory receptors such as the non-classical major histocompatibility complex class I (MHC-I) molecules HLA-E and HLA-G, the immune checkpoint ligands PDL1, PDL2, CD80 (B7-1), and CD86 (B7-2), cytokines IL-10, TGF beta, and C-C motif chemokines CCL 2/3/4/5/20. In addition, TAMs are directly involved in inhibiting T cell cytotoxicity through the expression of arginase 1, which leads to the depletion of L-arginine (essential for re-expression of the T cell receptor). A worthwhile goal should be TAMs in cancer therapy. Promising strategies are being tested as monotherapies or combination therapies with chemotherapy and immunotherapy, where anti-TAM drugs that are targeted towards the processes of recruitment (CCL2, CCR2, CSF1R), survival (CSF1R, caspase 8, bisphosphonates), or reprogramming (CD47, CD40, TLR7, CSF1R) of the macrophages should show their effect. We need more understanding to unravel the negative properties of TAMs in tumorigenesis and tumor progression.

This Special Issue is led by Dr. Pierre Tennstedt and assisted by our Topical Advisory Panel Member Dr. Shilpi Giri (University of Rochester Medical Center).

Dr. Pierre Tennstedt
Guest Editor

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Keywords

  • tumor-associated macrophages
  • tumor microenvironment
  • monocytes
  • cancer
  • cancer therapy
  • bisphosphonates
  • cytokines
  • chemokines
  • immune response
  • therapeutic resistance
  • immunotherapy

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Published Papers (3 papers)

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Research

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16 pages, 1236 KiB  
Communication
Chemoradiation-Altered Micromilieu of Glioblastoma Cells Particularly Impacts M1-like Macrophage Activation
by Mona Shojaei, Benjamin Frey, Florian Putz, Rainer Fietkau, Udo S. Gaipl and Anja Derer
Int. J. Mol. Sci. 2025, 26(14), 6574; https://doi.org/10.3390/ijms26146574 - 8 Jul 2025
Viewed by 321
Abstract
Glioblastoma is a highly aggressive brain tumor with an overall poor prognosis due to its immunosuppressive tumor microenvironment (TME). Microglia and tumor-associated macrophages (TAMs) with pro-tumorigenic properties are dominant populations of immune cells in the glioblastoma TME. To date, several studies targeting TAMs [...] Read more.
Glioblastoma is a highly aggressive brain tumor with an overall poor prognosis due to its immunosuppressive tumor microenvironment (TME). Microglia and tumor-associated macrophages (TAMs) with pro-tumorigenic properties are dominant populations of immune cells in the glioblastoma TME. To date, several studies targeting TAMs to fight tumor progression in different tumor entities have been initiated. However, the impact of standard therapy schemes of glioblastoma cells on macrophage polarization, activation, and phagocytosis remains controversial. The same applies to the relevance of PD-1/PD-L1 blockade in the interaction between macrophages and tumor cells. Our study, therefore, investigated patient-oriented treatment of GLIOBLASTOMA by examining the phagocytic capacity of polarized M1- and M2-like macrophages using GL261-luc2 tumor cells as a preclinical model system. Additionally, we analyzed the expression of activation and immune checkpoint markers on these macrophage subtypes following contact with tumor cells and their microenvironment. These factors were also determined after PD-1 blockade was initiated. The analyses revealed that the immunoregulatory M2-like macrophages generally exhibited a higher phagocytosis rate than the pro-inflammatory M1-like macrophages; however, this was not influenced by the pretreatment of glioblastoma cells with chemo- or radiotherapy. This could not be improved by blocking the PD-1 receptor. Furthermore, there were no modulations in the expression of differentiation, activation, or immune checkpoint molecules of M1- and M2-like macrophages after cell-to-cell contact with glioblastoma cells. But the medium conditioned by tumor cells strongly altered M1-like macrophages toward a more activated state, whereas M2-like cells were only mildly influenced. This was further enhanced by tumor cell treatment, with the most prominent effect after irradiation. These results suggest that conventional GLIOBLASTOMA tumor cell treatment affects the immunogenic status of macrophage subtypes, which is relevant for enhancing the anti-tumor immune response in brain tumors. Full article
(This article belongs to the Special Issue The Role of Macrophages in Cancers)
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17 pages, 4061 KiB  
Article
Bone Marrow Origin of Mammary Phagocytic Intraductal Macrophages (Foam Cells)
by Sanford H. Barsky, Krista Mcphail, Justin Wang, Robert M. Hoffman and Yin Ye
Int. J. Mol. Sci. 2025, 26(4), 1699; https://doi.org/10.3390/ijms26041699 - 17 Feb 2025
Cited by 1 | Viewed by 877
Abstract
Mammary intraductal macrophages (foam cells) in humans are the most commonly encountered cells in spontaneous breast nipple discharge, nipple aspirate fluid, and ductal lavage, yet their origin remains unproven. These cells, in both humans and murine model systems, increase in pregnancy, pseudopregnancy, and [...] Read more.
Mammary intraductal macrophages (foam cells) in humans are the most commonly encountered cells in spontaneous breast nipple discharge, nipple aspirate fluid, and ductal lavage, yet their origin remains unproven. These cells, in both humans and murine model systems, increase in pregnancy, pseudopregnancy, and other conditions like proliferative fibrocystic disease and intraductal neoplasia, ductal carcinoma in situ (DCIS), where there is intraductal ectasia and obstruction. Previous immunocytochemical studies with macrophage (CD68, lysozyme), epithelial (cytokeratin, estrogen receptor), and myoepithelial (smooth muscle actin, CALLA, maspin) markers have indicated that intraductal foam cells are of macrophage lineage. These foam cells engage in phagocytosis of both endogenous and exogenous substances present within the ducts and are not proliferative. Although it has been suggested that foam cells could derive from tissue-specific and niche-specific precursors or circulating monocytes, to date no experimental nor clinical studies have provided direct proof of their origin. In this study, we provide evidence in both human and murine bone marrow transplant studies that intraductal foam cells are bone marrow-derived. We first studied a registry of sex-mismatched bone marrow transplant recipients who later in life had undergone breast biopsies for either proliferative fibrocystic disease, DCIS, or gynecomastia, and studied these biopsies by XY chromosome fluorescence in situ hybridization (FISH) and informative microsatellite polymorphic markers. The intraductal foam cells were of bone marrow donor-origin. Then, in the experimental bone marrow transplant murine studies, donor marrow from female ROSA26 containing the lacZ reporter were transplanted into either irradiated female recipient transgenic mice carrying the highly penetrant MMTV-pymT or FVB/N background mice, where induced pluripotent stem (iPS) cells derived from tail vein fibroblasts of FVB/N-Tg(MMTV-PyVT)634Mul/J mice were subsequently injected into their mammary fat pads. In all of the transplanted recipient mice, the intraductal foam cells expressed the β-galactosidase (lacZ) reporter and also co-expressed markers of myeloid–macrophage lineage. The number of donor-derived intraductal foam cells increased in pseudopregnancy 5-fold and in intraductal neoplasia 10-fold. Although macrophages of different origins and lineages are undoubtedly present within both the murine and human breasts, those macrophages that qualify as phagocytic intraductal foam cells are bone marrow-derived. Full article
(This article belongs to the Special Issue The Role of Macrophages in Cancers)
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Review

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55 pages, 2579 KiB  
Review
Regulation and Function of Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): The Role of the SRIF System in Macrophage Regulation
by Agnieszka Geltz, Jakub Geltz and Aldona Kasprzak
Int. J. Mol. Sci. 2025, 26(11), 5336; https://doi.org/10.3390/ijms26115336 - 1 Jun 2025
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Abstract
Colorectal cancer (CRC) remains the leading cause of morbidity and mortality for both men and women worldwide. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) of solid tumors, including CRC. These macrophages are found in the pro-inflammatory [...] Read more.
Colorectal cancer (CRC) remains the leading cause of morbidity and mortality for both men and women worldwide. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) of solid tumors, including CRC. These macrophages are found in the pro-inflammatory M1 and anti-inflammatory M2 forms, with the latter increasingly recognized for its tumor-promoting phenotypes. Many signaling molecules and pathways, including AMPK, EGFR, STAT3/6, mTOR, NF-κB, MAPK/ERK, and HIFs, are involved in regulating TAM polarization. Consequently, researchers are investigating several potential predictive and prognostic markers, and novel TAM-based therapeutic targets, especially in combination therapies for CRC. Macrophages of the gastrointestinal tract, including the normal colon and rectum, produce growth hormone-releasing inhibitory peptide/somatostatin (SRIF/SST) and five SST receptors (SSTRs, SST1-5). While the immunosuppressive function of the SRIF system is primarily known for various tissues, its role within CRC-associated TAMs remains underexplored. This review focuses on the following three aspects of TAMs: first, the role of macrophages in the normal colon and rectum within the broader context of macrophage biology; second, the various bioactive factors and signaling pathways associated with TAM function, along with potential strategies targeting TAMs in CRC; and third, the interaction between the SRIF system and macrophages in both normal tissues and the CRC microenvironment. Full article
(This article belongs to the Special Issue The Role of Macrophages in Cancers)
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