Reprogramming Tumor-Promoting Macrophages: A New Frontier in Cancer Therapy

Figure 1: M1-like macrophage vs. M2-like macrophage at opposite ends of a continuous tumor associated macrophage spectrum, each playing different roles in the tumor microenvironment [1].

Written by Valerie Xu ‘28

Edited by Matthew Lam ‘27

How are tumor associated macrophages (TAMs) manipulated to support tumor progression —their role supposed to act as the body's first line of defense—and what are the therapy options?

Macrophages are white blood cells that play a crucial role in the immune system by detecting, engulfing, and destroying pathogens and other threats. However, within the tumor microenvironment, these immune cells undergo a dramatic transformation. Instead of acting as defenders, they are reprogrammed into tumor-associated macrophages (TAMs), which promote tumor growth and survival. This shift occurs because tumors release chemoattractants such as M-CSF (CSF1), CCL2, and VEGF, which actively recruit TAMs into the tumor tissues.

Once inside the tumor, TAMs contribute to drug-resistance and radio-protective effects, making cancer treatments less effective. Clinical studies have shown that higher TAM levels correlate with therapy failure and poorer prognosis in cancer patients. Given their profound impact on cancer progression, targeting TAMs has become a promising area of research. Current strategies focus on four key approaches: inhibiting macrophage recruitment, suppressing TAM survival, enhancing M1-like tumoricidal activity of TAMs, and blocking M2-like tumor-promoting activity of TAMs.

Targeting macrophage recruitment can be achieved by disrupting the actions of key chemoattractants. One such chemoattractant draws monocytes—white blood cells that destroy germs and bacteria—into the tumor microenvironment.  Tumors exploit monocytes by overexpressing chemoattractants which recruit monocytes to the tumor, where they differentiate into TAMs, promoting tumor survival and suppressing immune responses.

Inhibiting these chemoattractants can prevent excessive macrophage infiltration. Studies show that targeting an overexpressed chemoattractant reduces TAM populations and slows tumor growth. Trabectedin, a clinically used drug for ovarian cancer and myxoid liposarcoma, a rare cancer that originates in fat cells, selectively eliminates monocytes before they enter tumors, preventing their differentiation into mature TAMs. This reduction in TAMs restores a more immune-responsive environment, making tumors more vulnerable to treatment.

Additionally, a phase II clinical study found that certain antibodies reduce macrophage infiltration by lowering the plasma level of chemoattractants. These inhibitors disrupt TAMs and weaken the tumor’s ability to evade the immune system.

By blocking macrophage recruitment, these strategies reduce tumor-associated immunosuppression and enhance immune cell activity, making cancer cells more responsive to treatment. When combined with traditional immunotherapy methods like checkpoint inhibitors, this treatment approach offers a promising, more responsive, and less toxic therapeutic strategy.

Another avenue of treatment is the suppression of TAMs. Two methods of killing TAMS include inducing apoptosis—cell death—and triggering immune cells to recognize and abolish TAMs. To induce apoptosis, chemical reagents can be used, including bisphosphonates, a group of drugs that limit the loss of bone density. Because of their toxicity to TAMs, bisphosphonates have risen as prominent drugs for macrophage depletion. One bisphosphonate known as zoledronic acid has been shown to be a clinical drug for breast cancers, supporting the importance of investigating bisphosphonates as potential TAM-targeted therapy options.

The other route is to deplete TAMS with immunotoxin-conjugated agents, or antibodies that are chemically linked to a toxin. The antibody binds to the cell surface of the TAM, and the toxin is internalized into the cell, killing it. In addition to inducing apoptosis, immune responses can be harnessed to target macrophages, where cytotoxic T lymphocytes recognize and attack their membrane molecules. Up-regulating, or increasing the expression of specific surface molecules on TAMs will enhance the activity of lymphocytes, thus using the body’s natural immune mechanisms to deplete TAMs.

A third category of TAM treatment includes enhancing the M1 tumoricidal activity of TAMs. M1 macrophages suppress tumor growth, while M2 macrophages promote tumor growth. While many TAMs exhibit immunosuppressive M2-like properties, many can become M1-like. It’s shown that when high levels of Th1 cytokines—molecules that contribute to immune responses—are present, M1 macrophages will be established. Thus, finding a way to convert TAMs into M-1 types is a treatment strategy that wields great potential [2]. Current research into this mechanism exists in the exploration of Lenvatinib. Lenvatinib is a multitarget kinase inhibitor, meaning it inhibits kinases that lead to tumor growth and cancer progression. It has proven to be an effective treatment of advanced hepatocellular carcinoma. In vitro studies have shown that Lenvatinib enhances M1 activity in macrophages to suppress liver cancer cell proliferation [3].

The fourth treatment strategy is blocking the M2 tumor-promoting activity of TAMs. Inhibiting the signals essential for M2 differentiation and in turn impairing pro-tumor effects is another strategy in development. Many different pathways control the state of TAMs, and the pharmacological effects of agents that inhibit these pathways can block the M2-like activity of TAMs. One strategy currently being researched is directly reducing the number of M2-like macrophages in tumor microenvironments. For example, Pexidartinik—an inhibitor of a ligand that a chemoattractant binds to—when used with sirolimus—an immunosuppressive drug that may hinder tumor growth—can inhibit the growth of unresectable sarcoma—cancers that originate in the bones and soft tissues [4]—and malignant peripheral nerve sheath tumors—tumors that develop in the protective coverings of nerves in the peripheral nervous system [5]—by decreasing the number of M2-like TAMs [2].

Tumor associated macrophages are destructive cells that promote the proliferation of tumors. However, current research argues they can be reprogrammed into tumor inhibitors, and even used in conjunction with immunotherapy to support better prognosis for patients. These qualities shed light on TAMs as a future cancer therapy lighting the path for better, less harmful treatment methods for people.

References

1. Wang S, Wang J, Chen Z, Luo J, Guo W, Sun L, et al. Targeting M2-like tumor-associated macrophages is a potential therapeutic approach to overcome antitumor drug resistance. npj Precis Onc. 2024 Feb 10;8(1):31.

2. Tang X, Mo C, Wang Y, Wei D, Xiao H. Anti‐tumour strategies aiming to target tumour‐associated macrophages. Immunology. 2013 Feb;138(2):93–104.

3. Sun, Peng et al. “Lenvatinib targets STAT-1 to enhance the M1 polarization of TAMs during hepatocellular carcinoma progression.” BMC cancer vol. 24,1 922. 30 Jul. 2024, doi:10.1186/s12885-024-12680-1

4. Mayo Clinic [Internet]. [cited 2025 Mar 10]. Sarcoma - Symptoms and causes. Available from: https://www.mayoclinic.org/diseases-conditions/sarcoma/symptoms-causes/syc-20351048

5. Penn Medicine - Abramson Cancer Center [Internet]. [cited 2025 Mar 10]. Malignant Peripheral Nerve Sheath Tumor | Penn Medicine. Available from: https://www.pennmedicine.org/cancer/types-of-cancer/sarcoma/types-of-sarcoma/soft-tissue-sarcoma/malignant-peripheral-nerve-sheath-tumor