Tools and Targets in Cancer: Macrophages’ Promising Role

Macrophages, the immune cells normally tasked with engulfing pathogens and dead cells, are among the most abundant immune cells found inside solid tumors. Their sheer numbers make them powerful players in cancer biology, but they often work for the wrong side. Tumor-associated macrophages, or TAMs, frequently adopt behaviors that shield cancer cells from immune attack, feed tumor growth, and pave the way for metastasis. A growing wave of research now treats these cells not just as obstacles to overcome but as tools that can be redirected, depleted, or engineered to fight cancer.

How Tumors Turn Defenders Into Allies

Macrophages exist on a functional spectrum. At one end sit so-called M1-polarized macrophages, which are pro-inflammatory and capable of killing tumor cells. At the other end are M2-polarized macrophages, which suppress immune responses, promote new blood vessel growth, and help tumors spread. Tumor environments are loaded with signals that push macrophages toward the M2 end of that spectrum, effectively converting immune defenders into accomplices.¹ M1-type macrophages promote inflammation and tumor cell destruction, while M2-type macrophages drive immune suppression, blood vessel formation, and metastasis.²

This conversion is not a random accident. Tumors actively recruit macrophages from the bloodstream using chemical attractants and then reprogram them through a combination of tumor-derived signals, low oxygen levels, and competition for nutrients.³ Once reprogrammed, TAMs do a lot of the tumor’s dirty work. They secrete molecules like TGF-β1 that directly stimulate cancer cell proliferation and invasion, as demonstrated in colorectal cancer research.⁴ The result is that one of the most abundant immune populations inside a tumor is actively helping it grow rather than trying to destroy it.

Not All TAMs Come From the Same Place

For a long time, researchers assumed that TAMs were mostly blood monocytes that migrated into the tumor and then changed their behavior. That picture has grown more complicated. In pancreatic cancer, for instance, two distinct sources of TAMs have been identified: inflammatory monocytes circulating in the blood and tissue-resident macrophages that were seeded during embryonic development. These two populations behave differently once inside the tumor. Monocyte-derived TAMs are better at sampling tumor proteins, while embryonically derived TAMs express higher levels of factors that promote the dense, fibrous tissue that pancreatic tumors are notorious for.⁵ The fact that TAMs from different origins do different jobs inside the tumor means a therapy that targets one population might miss the other entirely.

Where a Macrophage Sits Matters as Much as What It Is

Advances in spatial profiling, which maps gene expression at precise locations inside tumor tissue, have shown that the behavior of both tumor cells and macrophages changes depending on their physical surroundings. A pan-cancer analysis of hundreds of tumor samples across a dozen cancer types found that macrophages sitting right next to tumor cells correlated with worse patient outcomes and resistance to immunotherapy, while macrophages clustered with other immune cells predicted better survival and better response to treatment.⁶

Similar findings have emerged in kidney cancer metastases. In that context, a neighborhood enriched for both TAMs and exhausted T cells was positively associated with immunotherapy response, while neighborhoods dominated by tumor cells with minimal immune infiltration tracked with disease progression.⁷ The practical takeaway is that simply counting macrophages in a tumor biopsy gives an incomplete picture. Their location and neighbors may be just as important for predicting how a patient will do on treatment.

TAM Density as a Prognostic Signal

Despite the spatial nuances, straightforward counts of certain TAM markers still carry real prognostic weight. In breast cancer, a higher density of macrophages bearing the CD204 marker was significantly associated with worse outcomes across several measures, including relapse-free survival, distant relapse-free survival, and disease-specific survival.⁸ In small cell lung cancer, patients whose tumors had high levels of the M2 marker CD163 had a median overall survival of roughly three months compared to about eight months for those with low CD163 counts.⁹

In oral squamous cell carcinoma, researchers found that macrophages positive for both CD163 and CD204 predicted unfavorable outcomes and promoted T-cell death through immune-suppressive molecules.¹⁰ Across these cancers, the pattern is consistent: more M2-like macrophages generally means worse news. This has fueled efforts to use TAM profiling as a clinical biomarker and, more ambitiously, to develop therapies that change the macrophage landscape within tumors.

Blocking the “Don’t Eat Me” Signal

Cancer cells protect themselves from macrophage phagocytosis by displaying a protein called CD47 on their surface. When CD47 binds its receptor SIRPα on a macrophage, it sends a signal that essentially says “don’t eat me.” Blocking this interaction unleashes macrophages to engulf cancer cells, and that initial act of phagocytosis can trigger a cascade: the macrophage processes tumor proteins and presents them to T cells, potentially kick-starting a broader adaptive immune response.¹¹ Drugs targeting this axis have shown encouraging results in preclinical work and have become a major focus for clinical development.¹²

CD47 is not the only “don’t eat me” signal that cancer cells use. Researchers have identified several additional phagocytosis checkpoints, including the CD24/SIGLEC-10 axis and the MHC-I/LILRB1 axis.¹³ LILRB1 recognizes a class of molecules found on virtually all human cells. When cancer cells display these molecules, they can inhibit phagocytosis much the same way CD47 does, which means that blocking CD47 alone may not be enough if the tumor has other shields in place. Targeting the LILRB1 axis could complement CD47 blockade and may also boost the activity of T cells and natural killer cells.¹⁴ The existence of multiple redundant escape routes is a reminder that tumors rarely rely on a single trick, and effective therapies may need to block more than one checkpoint at a time.

Depleting TAMs by Cutting Their Supply Line

Rather than trying to unshackle macrophages, another approach is to starve tumors of their macrophage workforce altogether. CSF1R is a receptor critical for macrophage survival and function, and inhibiting it can dramatically reduce the number of macrophages inside a tumor. In animal models, CSF1R inhibition led to a sharp drop in TAMs and a corresponding increase in the ratio of tumor-killing T cells.¹⁵ When one CSF1R-targeting antibody was given to patients, it produced striking reductions in immunosuppressive macrophages in tumor tissue and clinical responses in patients with a rare tumor type called diffuse-type giant cell tumor.

CSF1R inhibitors have also shown value in overcoming resistance to other cancer therapies. When tumors became resistant to anti-VEGF therapy, a treatment that blocks blood vessel growth, adding a CSF1R inhibitor restored responsiveness. In one preclinical experiment, mice that received the CSF1R inhibitor after resistance emerged had little to no measurable tumor remaining, while those that did not still had substantial disease. When the CSF1R inhibitor was combined with both anti-VEGF therapy and chemotherapy, tumor burden dropped by about 83% compared to the two-drug combination alone.¹⁶ Beyond simple depletion, CSF1R inhibitors have been shown to boost the phagocytic activity of remaining macrophages and reduce their production of immune-suppressive molecules.¹⁷

Reprogramming Macrophages Instead of Removing Them

Depletion has a downside: you lose the macrophages entirely, including any anti-tumor potential they might contribute if switched to the right mode. That has motivated a parallel line of research focused on repolarizing M2-like TAMs back toward an M1-like, tumor-killing state. A compound called R848, which activates toll-like receptors TLR7 and TLR8 on immune cells, has proven to be a potent driver of the M1 phenotype. Delivered via nanoparticles to concentrate it inside tumors, R848 shifted the entire immune landscape of the tumor toward an inflammatory, anti-tumor orientation in multiple mouse models. Treated animals showed controlled tumor growth and were even protected against future tumor challenge.¹⁸

More recent work has refined the delivery vehicle. A nanoplatform built from hollow manganese dioxide shells loaded with R848 pushed M2 macrophages toward M1 far more effectively than free R848 alone. Flow cytometry showed that the nanoplatform increased M1-marker-positive cells to about 28% while dropping M2-marker-positive cells to roughly 4%, compared to about 13% and 20% respectively for free R848.¹⁹ The nanoparticle shell not only delivered the drug more efficiently but appeared to have its own immune-stimulating effects that worked in combination with R848.

Repolarization signals can also come from an unexpected source: the microbiome. Certain gut bacteria appear to influence macrophage behavior inside tumors through their metabolic products. In pancreatic cancer, patients who had a higher abundance of a bacterial genus called Blautia tended to have better outcomes. Researchers traced this to a specific metabolite, 6-hydroxyhexanoic acid, which pushed macrophages from an M2 toward an M1 phenotype in both cell experiments and animal models.²⁰ The broader idea that microbial communities can shape macrophage polarization through metabolic pathways and immune signaling has attracted growing interest.²¹

Engineering Macrophages as Living Therapeutics

CAR-T cell therapy, in which a patient’s T cells are engineered with receptors that recognize tumor proteins, has transformed treatment for certain blood cancers but has struggled against solid tumors. Solid tumors create physical and chemical barriers that T cells have trouble penetrating. Macrophages, by contrast, naturally infiltrate solid tumors in large numbers, which makes them an appealing chassis for the same kind of engineering. CAR-macrophages, still in early clinical development, carry chimeric antigen receptors that direct them to recognize and attack tumor cells. While only one clinical trial was underway as of recent reporting, the potential advantages over CAR-T cells include better tumor infiltration and a wider range of anti-tumor mechanisms.²²

A separate engineering approach uses macrophage membranes as cloaking material for drug-carrying nanoparticles. Because macrophage membranes carry surface proteins that the immune system recognizes as “self,” wrapping a nanoparticle in macrophage membrane helps it evade immune clearance. The membrane also retains the macrophage’s natural tendency to home toward inflamed and tumor tissue, giving the nanoparticle built-in targeting ability.²³ One such design paired macrophage-membrane coating with a drug release mechanism triggered by conditions inside the tumor, achieving enhanced anti-tumor effects in preclinical testing.²⁴ The concept has been extended to other drug payloads, including curcumin-loaded nanoparticles tested in a colon cancer model.²⁵

Combining Macrophage-Targeted Therapies With Checkpoint Inhibitors

Many researchers believe that macrophage-directed approaches will ultimately work best in combination with existing immunotherapies. A clinical trial called MARIO-3 tested a drug called eganelisib, which targets a lipid-signaling enzyme involved in immune suppression, alongside checkpoint inhibitors and chemotherapy in patients with metastatic triple-negative breast cancer. Tumor biopsies taken before and during treatment showed gene signatures of TAM reprogramming, broader immune activation, and reorganization of the structural tissue surrounding tumors. Patients whose tumors initially lacked the PD-L1 marker, a group that typically responds poorly to checkpoint inhibitors alone, showed elevated structural tissue signatures at baseline that decreased with treatment, while immune activation signatures appeared regardless of PD-L1 status and tracked with longer progression-free survival.²⁶

The logic behind combination approaches is straightforward. Checkpoint inhibitors work by releasing the brakes on T cells, but T cells cannot do their job if macrophages are still suppressing the immune environment. Adding a macrophage-targeted therapy could remove that suppressive layer and allow T cells to function more effectively. The MARIO-3 data suggest that this kind of combination can reshape the tumor environment in measurable ways, though translating those molecular changes into survival benefits across larger patient populations is the next hurdle.

How Tumors Use Macrophages to Prepare Distant Organs for Metastasis

One of the more unsettling discoveries in recent years is that tumors can corrupt macrophages at a distance, in organs they have not yet spread to. Colorectal cancers, for instance, release tiny membrane-enclosed packages called extracellular vesicles into the bloodstream. These vesicles carry specific molecular cargo that, once absorbed by macrophages in the liver, reprograms them into a pro-tumor state. In one study, vesicles enriched with a particular circular RNA molecule were absorbed by liver macrophages and activated a subtype of macrophages that reshaped the liver’s tissue environment to become hospitable for incoming cancer cells, promoting the eventual formation of metastases.²⁷

This concept of a “pre-metastatic niche,” a landing pad prepared in advance by the primary tumor, puts macrophages at the center of metastasis in a way that goes beyond their role at the primary tumor site. It also opens a potential therapeutic window: intercepting these extracellular vesicles or blocking their effects on distant macrophages could, in theory, prevent metastasis before it takes hold. That idea is still largely preclinical, but it represents an entirely different angle on the macrophage problem, one focused on prevention rather than treatment of existing disease.