Eosinophils and Cancer: A Complex Relationship

Eosinophils, white blood cells best known for fighting parasites and fueling allergic reactions, turn out to play a surprisingly varied role in cancer. Depending on the tumor type, the surrounding tissue environment, and even where within a tumor they accumulate, eosinophils can either help destroy cancer cells or inadvertently promote their spread. This duality has made them one of the more puzzling immune players in oncology, and recent research into immunotherapy has only deepened the intrigue.

How Eosinophils End Up Inside Tumors

Eosinophils don’t just wander into tumors by accident. They’re actively recruited by chemical signals, particularly a family of molecules called eotaxins, first identified in 1994 as selective eosinophil attractants.¹ The best studied of these, CCL11 (also known as eotaxin-1), is produced by certain tumor cells and surrounding tissue. When the signal is strong enough, eosinophils migrate from the bloodstream into the tumor mass. Some tumors, however, actively suppress this recruitment. In pancreatic cancer, for instance, a signaling molecule called autotaxin blocks the production of CCL11 by interfering with a transcription factor that normally drives its expression, essentially silencing the call for eosinophils.² The fact that certain cancers have evolved ways to keep eosinophils out suggests these immune cells pose a real threat when they arrive.

The Anti-Tumor Side

When eosinophils do infiltrate a tumor, they can mount a surprisingly effective defense. They carry granules packed with toxic proteins and can generate reactive oxygen species, both of which are directly harmful to cancer cells. But their most important anti-tumor contribution may be indirect. Research in mouse models has shown that eosinophils homing to tumors secrete chemical signals that attract CD8+ T cells, the immune system’s primary cancer-killing cells. Once those T cells arrived, tumors were eradicated and the animals survived.³ In that same work, eosinophils also normalized the abnormal blood vessels that typically form inside tumors. Tumors deliberately grow leaky, disorganized vasculature that makes it hard for immune cells to get in. By helping to restructure those vessels, eosinophils essentially opened the door for the rest of the immune system.

This orchestrating role goes beyond simple direct killing. Eosinophils are increasingly recognized as connectors between different arms of the immune response within tumors, capable of reshaping the local environment to favor immune attack rather than immune evasion.

The Pro-Tumor Side

The picture flips in certain cancers. In head and neck squamous cell carcinoma (HNSCC), tumor-associated tissue eosinophils have been linked to worse outcomes. Research found that eosinophils in these tumors promoted angiogenesis, the growth of new blood vessels that feed the tumor, and were correlated with increased metastasis.⁴ In other words, the same cell type that normalized blood vessels in one cancer context actively built harmful new ones in another.

Adding another layer, eosinophils can release web-like structures called eosinophil extracellular traps (EETs), somewhat analogous to the DNA nets that neutrophils cast. In HNSCC, these traps have been associated with both anti-cancer immune pathways and pro-tumor processes like proliferation and migration, depending on the molecular context.⁵ The same structure, in other words, can cut both ways. Researchers are still working out what tips the balance in one direction or the other, but the tumor’s molecular makeup and the signals it sends to eosinophils appear to be key factors.

What Determines Which Side Wins

The fundamental question, why eosinophils help in some cancers and harm in others, doesn’t have a clean answer yet. But context matters enormously. Eosinophils are not a single uniform population. Advances in single-cell profiling have revealed that eosinophils arriving in tumors can take on different functional states depending on the signals they encounter. They carry the molecular toolkit for both cytotoxicity and tissue remodeling, and the tumor microenvironment appears to dictate which tools get used. Cancer type is one obvious variable: solid tumors in the gut, skin, and lungs tend to show positive associations with eosinophil infiltration, while certain head and neck cancers show the opposite pattern. But even within a single cancer type, the specific molecular subtype and the broader immune landscape surrounding the tumor likely matter.

Eosinophils as a Prognostic Sign in Solid Tumors

Despite the complexity, the general trend across most solid tumors is encouraging. A meta-analysis pooling data from multiple cancer types found that eosinophil infiltration was associated with better overall survival, with particularly strong associations in esophageal cancer and colorectal cancer.⁶

The colorectal cancer evidence is especially detailed. In a large cohort study, patients whose tumors had the highest levels of eosinophil infiltration in the tissue surrounding the cancer (called the stroma) had roughly half the risk of dying from colorectal cancer compared to those with the lowest levels. The benefit was most apparent in intermediate-stage disease.⁷ These aren’t small differences. A halving of cancer-specific mortality is the kind of signal that catches oncologists’ attention, even though eosinophil counts aren’t yet part of standard staging systems.

In melanoma, the pattern holds in a different way. Patients who developed eosinophilia, an elevated eosinophil count in the blood, at any point during their disease course showed a trend toward longer survival. Among those who survived at least a year, the difference was statistically clear. Even more striking, patients with very high eosinophil counts (above 20%) had a median survival of 35 months, compared to 16 months for those without such high levels.⁸

Where Eosinophils Sit Within the Tumor Matters

A simple eosinophil headcount doesn’t tell the whole story. Researchers have known for some time that the spatial distribution of eosinophils within a tumor can be just as important as how many are present. In colon cancer, an early study found something unexpected: when eosinophils were abundant enough to indicate a good prognosis, their concentrations were actually lower at the tumor’s outer margin and higher deeper within the tumor mass. This was a novel finding at the time, as most inflammatory cells are more concentrated at a tumor’s edges.⁹ Patients whose tumors had higher eosinophil concentrations, whether measured at the margin or deeper in, were less likely to have metastases.

More recent computational work has refined this picture. Using algorithms that map immune cell positions relative to tumor cells, researchers have shown that tumors with similar overall eosinophil densities can fall into distinct spatial subtypes, such as “cold, stroma-rich” versus “cold, tumor-rich,” and these subtypes can have different survival associations.¹⁰ Two tumors might each contain the same number of eosinophils, but if one has them clustered near blood vessels while the other has them scattered among cancer cells, the clinical implications could differ. This kind of spatial nuance is one reason simple blood tests for eosinophil counts, while useful, can only approximate what’s happening at the tissue level.

Eosinophils and the Immunotherapy Revolution

The connection between eosinophils and cancer has become clinically relevant in a new way with the rise of immune checkpoint inhibitors, drugs like pembrolizumab and nivolumab that release the brakes on the immune system. Researchers have been looking for simple, inexpensive blood tests that might predict who will respond to these treatments, and eosinophil counts have emerged as a candidate.

In non-small cell lung cancer, patients starting checkpoint inhibitor therapy with higher baseline blood eosinophil counts had a higher response rate (about 41% versus 29%) and longer progression-free survival (roughly 9 months versus 6 months) compared to those with lower counts.¹¹ A separate analysis found that pretreatment eosinophil counts in a moderate range were associated with the longest overall survival in lung cancer patients on checkpoint inhibitors.¹²

In melanoma, the overlap between eosinophilia and immunotherapy response is especially notable. Among melanoma patients receiving checkpoint inhibitors, about 69% developed blood eosinophilia at some point during treatment, compared to 46% of those not receiving immunotherapy. Every patient who developed eosinophilia while on checkpoint inhibitor therapy had significantly prolonged survival.⁸

The pattern isn’t universal, though. In recurrent or metastatic head and neck cancer, a study found the opposite: lower eosinophil counts and percentages were linked to better survival and higher response rates to checkpoint inhibitors.¹³ This echoes the earlier finding that eosinophils play a pro-tumor role in some head and neck cancers and underscores why no single eosinophil rule applies across all cancer types.

Eosinophilia as a Side Effect of Immunotherapy

Checkpoint inhibitors can cause eosinophil counts to spike as a treatment side effect, and this isn’t always benign. In a French national reference center study examining moderate-to-severe eosinophilia triggered by checkpoint inhibitor therapy, over half of the cases involved an immune-related adverse event linked to the eosinophil surge, such as skin reactions, lung inflammation, or organ damage.¹⁴ So while eosinophilia during immunotherapy often correlates with a better anti-tumor response, it can simultaneously signal tissue damage from an overactive immune system. Clinicians face a balancing act: the same immune activation that fights the cancer can harm healthy organs.

In kidney cancer patients treated with combination checkpoint inhibitor regimens, having a baseline eosinophil proportion of 2% or higher independently predicted a higher risk of serious treatment-related side effects, with roughly double the odds of developing grade 3 or worse adverse events.¹⁵ Knowing this ahead of time could help oncologists monitor high-eosinophil patients more closely or adjust their treatment plans accordingly.

When Eosinophils Themselves Become Cancer

There’s another dimension to the eosinophil-cancer relationship that’s entirely different from what happens in solid tumors. In rare cases, eosinophils themselves can become malignant. Chronic eosinophilic leukemia is a type of blood cancer in which eosinophils multiply uncontrollably. One specific subtype is driven by a gene fusion called FIP1L1-PDGFRα, which produces an abnormal protein that tells eosinophils to keep dividing. The resulting mass of eosinophils releases granule contents, cytokines, and other inflammatory molecules that damage the heart, lungs, skin, and other organs.¹⁶ This condition is quite rare, but it’s an important reminder that eosinophils aren’t always the heroes of the immune story. When their growth becomes unregulated, the same toxic granule proteins that can kill cancer cells in solid tumors instead cause widespread tissue destruction.

Could Anti-Eosinophil Drugs Affect Cancer Risk

Millions of people now take biologic drugs that target eosinophils for conditions like severe asthma, chronic sinusitis, and eczema. Medications like mepolizumab, benralizumab, and dupilumab either deplete eosinophils or block the signals that sustain them. Given that eosinophils appear to help fight cancer in many solid tumor contexts, a natural concern is whether suppressing them could increase cancer risk.

A pharmacovigilance analysis of the FDA’s adverse event reporting system identified thousands of neoplasm-related reports among users of anti-type 2 biologic drugs. The most commonly reported cancers across these drugs were breast cancer, lung cancer, and prostate cancer.¹⁷ However, adverse event databases can’t establish causation. The people taking these drugs tend to be older and have chronic inflammatory conditions, both of which are independent cancer risk factors. Still, the volume of reports has prompted attention, and long-term safety surveillance continues. For patients currently on these medications, the evidence doesn’t warrant stopping treatment, but it’s a legitimate area of ongoing research.

The Gut Microbiome Connection

An emerging line of research connects eosinophil behavior in tumors to signals originating far from the cancer itself, specifically in the gut. The gut microbiota communicates with eosinophils through what researchers describe as a neuroimmune axis, involving the vagus nerve, neurotransmitters, and small signaling molecules produced by gut bacteria. This communication network appears to influence how eosinophils form extracellular traps and how they behave once they reach the tumor microenvironment.¹⁸ The clinical implications are still speculative, but the idea that your gut bacteria might influence how effectively your eosinophils fight a tumor in your lung or colon is the kind of cross-system connection that has reshaped thinking in cancer immunology. If the microbiome does modulate eosinophil function during immunotherapy, it could eventually help explain why some patients respond dramatically to checkpoint inhibitors while others don’t.

Eosinophil Heterogeneity and the Research Frontier

One reason eosinophils have been historically overlooked in cancer research is that they were treated as a single, monolithic cell type. That view is changing rapidly. Single-cell technologies now reveal that eosinophils arriving in the tumor microenvironment are heterogeneous, carrying different surface markers and functional capabilities. Some subsets appear primed for cytotoxicity, armed with granule proteins and reactive oxygen species ready to attack cancer cells. Others seem oriented toward tissue remodeling or immune signaling, with the potential to either amplify or dampen the broader immune response depending on context. This heterogeneity helps explain why overall eosinophil counts in the blood or tumor give an incomplete picture. Two patients might have the same number of eosinophils in their tumors but very different mixes of eosinophil subtypes, leading to different outcomes.

Researchers are now working to identify which eosinophil subtypes are the beneficial ones and whether treatments could selectively expand or recruit those populations while limiting pro-tumor variants. This is technically challenging, since eosinophils are fragile cells that are difficult to study with many standard laboratory methods, and they make up a small fraction of the immune cells in most tumors. But the payoff could be significant: if clinicians could reliably distinguish “good” eosinophil infiltration from “bad” in a biopsy sample, it would add a new dimension to treatment planning that goes beyond simply counting these cells in a blood draw.