image: Effects of senescent macrophages on tumors. (A) Inflammation: senescent macrophages secrete factors, such as IL-6, IL-8, and IL-1α, that form the SASP, which establishes an immunosuppressive environment. SASP factors activate NF-κB, thus promoting MDSC and Treg infiltration, suppressing T and B cell functions, and advancing tumor progression. (B) Polarization: aging macrophages often polarize to the M2 phenotype, which promotes tumor progression through expression of IL-10, Arg1, and CD163, thereby enhancing angiogenesis and immune evasion. (C) Metabolic changes: aging macrophages show diminished NAD+ levels, impaired phagocytosis, and mitochondrial dysfunction. Lactate accumulation maintains the M2 phenotype and promotes tumor survival, whereas mitochondrial damage and oxidative stress worsen inflammation via NLRP3 activation. (D) Infiltration: increased CCR2 expression in senescent macrophages enhances their response to tumor-secreted chemokines (CCL2 and VEGF) and leads to stronger infiltration and tumor progression. (E) Phagocytosis: senescent macrophages show impaired phagocytosis because of IL-10 secretion by peritoneal B cells and decreased scavenger receptor expression, such as Mrc1, thus weakening tumor-clearing ability. Additionally, dysregulation of circadian genes, such as Klf4, worsens functional decline, impairs tumor suppression, and promotes tumor development, thus affecting treatment outcomes. SASP, senescence-associated secretory phenotype; IL, interleukin; MMPs, matrix metalloproteinases; MDSCs, myeloid-derived suppressor cells; EMT, epithelial-mesenchymal transition; NAD, nicotinamide adenine dinucleotide; ROS, reactive oxygen species; NLRP3, NOD−, LRR− and pyrin domain-containing protein 3; VEGF, vascular endothelial growth factor; CCL2, C-C motif chemokine ligand 2; CCR2, C-C motif chemokine receptor 2.
Credit: Cancer Biology & Medicine
Aging immune cells known as senescent macrophages are emerging as critical players in cancer progression. Rather than defending the body, these aged cells undergo profound functional shifts that support tumor growth—spreading inflammation, suppressing immunity, and remodeling tissue. This review brings together a wide range of evidence to clarify the molecular pathways behind these changes, identifying key markers and mechanisms that link senescence to cancer. It also maps out a new frontier in treatment: targeting senescent macrophages with senolytics, senomorphics, and senoreverters—offering hope for reversing the harmful effects of aging within tumors.
Macrophages are versatile immune cells, tasked with cleaning up pathogens and maintaining tissue health. But within the tumor microenvironment, they often shift into an M2-like state—one that paradoxically helps tumors grow by weakening immune defenses and promoting inflammation. At the same time, cellular senescence, traditionally seen as a tumor-suppressive mechanism, can have the opposite effect in aged macrophages. These cells become chronic sources of inflammatory signals and lose their ability to destroy cancer cells. Because of these complexities, there is an urgent need to study senescent macrophages more deeply to uncover their full impact on cancer biology.
A new review published (DOI: 10.20892/j.issn.2095-3941.2024.0589) in Cancer Biology & Medicine by researchers at Shandong University takes an in-depth look at how aging macrophages—once thought to be passive bystanders—actively drive tumor development. Drawing on molecular biology, immunology, and emerging therapeutic strategies, the authors present the first comprehensive framework linking macrophage senescence to cancer. The study not only details the functional shifts that occur in these cells but also explores a range of cutting-edge treatments—including drugs that eliminate or reprogram them—offering new possibilities for cancer therapy.
Senescent macrophages undergo dramatic changes: they lose their tumor-fighting abilities and instead foster a microenvironment ripe for cancer growth. Marked by elevated levels of p16INK4a, p21, and SA-β-gal, these cells secrete pro-inflammatory factors like IL-6, IL-10, and VEGF, while exhibiting reduced antigen presentation and phagocytosis. Their shift toward an M2-likephenotype is accompanied by metabolic dysfunction and increased tissue infiltration—traits that undermine immune surveillance and promote metastasis. The review outlines three therapeutic approaches: senolytics, which selectively remove senescent macrophages; senomorphics, which suppress their harmful secretions (SASP); and senoreverters, which attempt to reverse their aged state. Promising agents include quercetin, fisetin, rapamycin, and even CAR-T cells designed to target aging markers. These treatments could reshape the tumor landscape by restoring immune balance and enhancing existing cancer therapies.
"Senescent macrophages have been overlooked for too long," said Dr. Chen Qiu, corresponding author of the study. "They're not just passive markers of aging—they actively reshape the tumor environment. By targeting these cells, we open up new therapeutic pathways that complement immunotherapies and could overcome treatment resistance. This is not just a new chapter—it's a whole new storyline in cancer research."
Therapeutic strategies that focus on senescent macrophages could play a transformative role in future cancer care. These aging cells are implicated in immune evasion and resistance to checkpoint inhibitors and chemotherapy. Combining senolytic or senomorphic treatments with standard therapies may enhance response rates and reduce recurrence. However, challenges remain: current biomarkers lack specificity, and senescent cells vary widely by tissue type. The review calls formulti-omics profilingand precision targeting to overcome these hurdles. As researchers decode the biology of aging within tumors, senescent macrophages may emerge not just as obstacles—but as strategic targets to tip the balance in favor of patients.
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References
DOI
10.20892/j.issn.2095-3941.2024.0589
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2024.0589
Funding information
This work was supported by grants from the Postdoctoral Science Foundation of China (Grant No. 2020M672072).
About Cancer Biology & Medicine
Cancer Biology & Medicine (CBM) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 8.4, 5-year IF 6.7), with all full texts freely visible to clinicians and researchers all over the world.
Journal
Cancer Biology & Medicine
Subject of Research
Not applicable
Article Title
Senescent macrophages in cancer: roles in tumor progression and treatment opportunities
Article Publication Date
6-May-2025
COI Statement
The authors declare that they have no competing interests.