Cancer immunotherapy has made major breakthroughs in recent years, but its full potential is still limited—especially for solid tumors. A new 2025 review published in Molecular Cancer by Rui Coelho and colleagues at the Erasmus MC Cancer Institute explores a critical reason for this limitation: a type of immune cell known as the tumor-associated macrophage (TAM). These cells, originally part of the body’s defense system, are often hijacked by tumors to suppress T cells—the immune system’s main cancer-killing soldiers. This article simplifies the key findings for a general audience and explains why targeting TAMs could hold the key to making cancer immunotherapies more powerful and long-lasting.
What Are Tumor-Associated Macrophages?
Macrophages are versatile immune cells that protect the body by engulfing harmful invaders and cleaning up damaged tissue. In tumors, these cells are known as TAMs. Early in cancer development, TAMs can fight the tumor by helping T cells recognize and attack cancer cells. However, as the disease progresses, tumors “reprogram” macrophages into a pro-tumor form that shields cancer cells and suppresses immune responses.
These pro-tumor TAMs become abundant in many cancers and are often linked to worse patient outcomes and reduced responses to immunotherapy. In other words, instead of helping, they create a hostile environment that weakens the very T cells therapy tries to activate.
How TAMs Weaken Cancer-Fighting T Cells
The interplay between T cells and TAMs determines whether the immune system can destroy cancer. Anti-tumor TAMs attract and stimulate T cells by producing helpful molecules and presenting tumor antigens for recognition. Pro-tumor TAMs, however, do the opposite—they release signals like IL-10 and TGF-β that block T cell entry into tumors and inhibit their function.
On a deeper level, TAMs can starve T cells of nutrients and produce metabolic byproducts, like adenosine, that act as chemical “brakes” on immune activity. They also display surface proteins known as immune checkpoints—such as PD-L1—that directly turn off T cells. These combined effects leave T cells “exhausted,” unable to fight effectively.
Breaking the Immune Suppression Cycle
Traditional immunotherapies, like checkpoint inhibitors or CAR-T cell therapy, focus on reviving T cells. But if TAMs remain suppressive, those T cells quickly lose strength again. That’s why scientists are now shifting attention toward reprogramming or blocking TAMs instead of simply trying to eliminate them.
Current research is uncovering several promising molecular targets on TAMs that could be drugged or engineered against. Coelho’s team highlights five key pathways that drive immune suppression within the tumor microenvironment:
- Aryl Hydrocarbon Receptor (AhR):
This molecule is activated by metabolites produced by TAMs from the amino acid tryptophan. Once activated, it increases T cell exhaustion and enhances tumor growth. Blocking AhR or the enzymes that fuel it (IDO1 and IL4I1) can restore T cell vigor and improve responses to checkpoint therapy in animal models. - Galectin-3 (Gal3):
Gal3 disrupts communication between T cells and tumor cells, preventing effective attacks. Drugs that block Gal3—like belapectin and GB1211—are already being tested in combination with PD-1 inhibitors to boost immune responses in cancer patients. - Siglec-9 and Siglec-15:
These “sugar sensors” on TAMs and tumor cells bind sialic acids—specific sugar molecules that often coat cancer cells. This interaction drives macrophages into anti-inflammatory, tumor-protective states. Blocking Siglec-9 or Siglec-15—or removing those sugars—can reawaken T cells and strengthen other immunotherapies. - B7-H4 and VISTA:
These are emerging immune checkpoint molecules mostly found on macrophages rather than tumor cells. They can suppress T cells even in cases where PD-1 and PD-L1 blockers fail, making them exciting non-overlapping targets. New antibodies, such as SNS-101 (targeting VISTA) and GEN1047 (targeting B7-H4), are currently being evaluated in clinical trials.
Why This Matters
The review emphasizes that TAMs are not simple villains—they exist along a spectrum from helpful to harmful. Completely removing macrophages may harm normal tissue repair and immune balance. Instead, the goal is to reprogram TAMs back into their anti-tumor state or protect T cells from their suppressive influence.
This shift in thinking could enhance existing immunotherapies. Combining T cell-based approaches like CAR-T therapy with drugs targeting TAM pathways might overcome resistance in cancers that haven’t responded to current treatments. It could also reduce side effects by allowing more precise control of the tumor immune environment.
The Road Ahead
Future research will focus on mapping which macrophage subtypes dominate in each cancer type and testing how specific inhibitors perform in patients. Advances in single-cell analysis and gene editing are already helping scientists uncover the complex molecular “conversations” between TAMs and T cells.
The authors suggest that one day, cancer-fighting T cells could be genetically engineered not only to recognize tumors but also to resist suppression by TAMs. This next generation of immunotherapy could finally turn the tide in solid tumor treatment, offering longer-lasting remission and broader benefits across patients.
In Summary
TAMs are double agents of the immune system—sometimes fighting cancer, often protecting it. Understanding and reprogramming these cells may be the missing piece to unlocking more effective, durable cancer immunotherapies. The emerging drug targets identified in this study, from AhR and Gal3 to Siglec-15 and VISTA, could soon form the foundation for combination treatments that restore the immune system’s full power against cancer.
