MDSCs, or myeloid-derived suppressor cells, are immune cells that shut down the body’s normal immune defenses. They belong to the myeloid family of blood cells, the same lineage that produces infection-fighting white blood cells. In healthy people, MDSCs are virtually undetectable in the bloodstream. But in cancer, chronic infections, and certain inflammatory conditions, they accumulate in large numbers and actively prevent the immune system from doing its job.
Understanding MDSCs has become a major focus in cancer research because these cells are one of the key reasons tumors can evade immune attack. They also help explain why some patients respond poorly to immunotherapy.
Where MDSCs Come From
All blood cells originate in the bone marrow. Under normal conditions, immature myeloid cells produced there mature into three types of functional immune cells: macrophages (which engulf pathogens), dendritic cells (which alert the rest of the immune system to threats), and granulocytes (which fight infections, especially bacterial ones). This maturation process runs smoothly in a healthy body, and the immature precursors don’t linger.
In disease states, particularly cancer, that maturation process stalls. Tumors and chronically inflamed tissues release signals that block these immature cells from finishing their development. Instead of becoming functional immune cells, they get stuck in an intermediate state and acquire the ability to suppress other immune cells. These stalled, suppressive cells are what researchers call MDSCs. They are not a distinct cell lineage but rather a collection of myeloid cells that have been pathologically activated and redirected toward immune suppression.
The Two Main Types
MDSCs come in two primary subtypes, each with somewhat different biology. The first is polymorphonuclear MDSCs (PMN-MDSCs), which resemble neutrophils, the most common white blood cells. The second is monocytic MDSCs (M-MDSCs), which resemble monocytes, the precursors to macrophages. A small third group called early-stage MDSCs (e-MDSCs) has also been identified, though it is less well characterized.
Distinguishing MDSCs from normal neutrophils and monocytes is one of the biggest challenges in the field. No single surface marker uniquely identifies an MDSC. Researchers currently rely on a combination of markers detected through a lab technique called flow cytometry, along with density-based separation methods and, critically, functional tests proving the cells actually suppress immune responses. A 2016 consensus paper published in Nature Communications laid out minimum criteria for identifying and reporting MDSCs, but the lack of a clean, definitive marker remains an obstacle in clinical research.
How MDSCs Suppress the Immune System
MDSCs use several biochemical strategies to disarm the immune cells that would otherwise attack a tumor or fight an infection. Their primary targets are T cells and natural killer cells, two of the body’s most important weapons against cancer.
One of their main tactics involves starving T cells of an amino acid called arginine, which T cells need to multiply and function. MDSCs produce high levels of an enzyme that breaks down arginine in the surrounding tissue, depleting it before T cells can use it. Without arginine, T cells lose a critical component of their signaling machinery and stop proliferating. MDSCs also deplete cysteine, another amino acid essential for T cell activation.
The two MDSC subtypes favor slightly different suppressive tools. Monocytic MDSCs primarily produce nitric oxide, a molecule that interferes with T cell signaling and can trigger T cell death. Polymorphonuclear MDSCs rely more on reactive oxygen species, highly reactive molecules that chemically alter the receptors on T cells, preventing them from recognizing their targets. When nitric oxide and reactive oxygen species combine, they form peroxynitrite, a particularly potent compound that scrambles the recognition system T cells use to identify cancer cells.
Beyond these direct attacks on T cells, MDSCs also produce anti-inflammatory signaling molecules that broadly dampen immune activity. They promote the expansion of regulatory T cells, another type of immune cell that suppresses immune responses, creating a compounding effect. Some MDSCs also display a surface molecule called PD-L1, which acts like an “off switch” when it contacts T cells, the same pathway that checkpoint immunotherapy drugs are designed to block.
Their Role in Cancer
MDSCs do far more than just suppress immunity. They actively help tumors grow and spread. Inside the tumor microenvironment, MDSCs secrete growth factors that directly stimulate cancer cell proliferation. They produce factors that promote the formation of new blood vessels to feed the tumor, a process called angiogenesis. And they release enzymes that break down the tissue surrounding a tumor, making it easier for cancer cells to invade neighboring tissue and enter the bloodstream.
Perhaps most concerning, MDSCs help establish what researchers call pre-metastatic niches. They travel to distant organs ahead of migrating cancer cells and reshape the local environment to make it hospitable for new tumors to take root. This means MDSCs are involved not just in helping a primary tumor survive but in enabling cancer to spread to new locations.
MDSCs as a Prognostic Marker
High MDSC levels in the blood consistently predict worse outcomes for cancer patients. A meta-analysis of 40 studies covering more than 2,200 patients with solid tumors found that patients with elevated circulating MDSCs before treatment had roughly 80% higher risk of death compared to patients with lower levels. The association held across cancer types, though the strength varied. Breast cancer showed the strongest link, with high MDSC levels tripling the risk of death. Liver cancer and melanoma also showed strong associations, with roughly 2.5 to 2.8 times higher risk.
The connection extends beyond overall survival. Patients with high MDSC levels were also significantly more likely to experience disease progression or recurrence after treatment, with roughly 2.5 times higher risk. Both MDSC subtypes predicted worse outcomes independently, though monocytic MDSCs showed a stronger association with poor survival than the polymorphonuclear type. These findings have fueled interest in using MDSC levels as a blood-based biomarker to help predict which patients might benefit most from aggressive treatment or immunotherapy combinations.
MDSCs Beyond Cancer
While cancer research dominates the MDSC field, these cells also accumulate in a range of non-malignant conditions, including chronic infections, sepsis, obesity, trauma, and autoimmune diseases. Their role in these contexts is more nuanced and sometimes even beneficial.
In autoimmune diseases like rheumatoid arthritis and multiple sclerosis, MDSCs appear to play a protective role in some cases. In animal models of rheumatoid arthritis, monocytic MDSCs reduced disease severity by suppressing the overactive T cell responses driving joint inflammation. Similarly, in models of multiple sclerosis, certain MDSC populations reduced the severity of the disease, particularly in its later phases. However, the picture is not straightforward. Some studies have found that MDSCs in autoimmune conditions can promote the development of a specific type of inflammatory T cell (Th17 cells) that actually worsens disease. Whether MDSCs help or harm in autoimmune conditions likely depends on the timing, the specific MDSC subtype involved, and the local tissue environment.
How MDSCs Fuel Themselves
MDSCs inside tumors undergo a metabolic shift that enhances their suppressive power. Normal immune cells typically rely on glucose as their primary fuel. Tumor-infiltrating MDSCs, however, switch to burning fatty acids as their main energy source. This shift is driven by an increase in fat uptake: MDSCs inside tumors ramp up the production of fat transport molecules on their surface, pulling in more fatty acids from their surroundings.
This fat accumulation is not just a side effect of being in a lipid-rich tumor environment. It directly enhances the cells’ ability to suppress T cells and block the immune system’s ability to recognize tumor proteins. In animal studies, drugs that block fatty acid burning in MDSCs improved anti-tumor immunity, suggesting this metabolic pathway could be a therapeutic vulnerability.
Targeting MDSCs in Treatment
Because MDSCs are a major barrier to effective anti-cancer immunity, eliminating or reprogramming them has become an active area of therapeutic development. Several strategies are being explored.
- Depleting MDSCs directly: Certain chemotherapy agents can selectively kill MDSCs, and antibody-based approaches targeting specific receptors on MDSC surfaces have shown promise in animal models. One approach uses antibodies that activate a cell-death receptor (DR5) found on MDSCs, selectively eliminating them without significant toxicity to the host.
- Forcing maturation: Compounds like all-trans retinoic acid (a derivative of vitamin A) can push MDSCs to complete their stalled development, converting them into normal, functional immune cells that no longer suppress T cells.
- Blocking recruitment: Inhibiting the signaling pathways tumors use to attract MDSCs can reduce their accumulation at tumor sites.
- Combination with immunotherapy: MDSC depletion has been shown to enhance the effectiveness of checkpoint immunotherapy drugs (like those targeting PD-L1) in preclinical models of gastric and colon cancers. The combination worked better than either approach alone, because removing MDSCs allowed T cells to infiltrate tumors and respond to the checkpoint blockade.
These combination strategies reflect a growing recognition that immunotherapy often fails not because the immune system lacks the ability to fight cancer, but because suppressive cells like MDSCs are actively holding it back. Removing that brake while simultaneously pressing the accelerator with checkpoint drugs is one of the most promising directions in cancer immunology.