Senescent macrophages emerge as key drivers of tumor progression

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 p16^INK4a, 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. 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."

Dr. Chen Qiu, corresponding author of the study

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.