Myeloid-Derived Suppressor Cells in Cancer: How MDSCs Block Immunotherapy

Myeloid-derived suppressor cells, or MDSCs, are becoming an important focus in cancer immunology because of the way they reshape the tumor microenvironment and weaken antitumor immune responses.

Rather than attacking cancer, these myeloid cells can suppress T-cell activity, support immune escape, and create conditions that make tumors harder to control. Their presence has also been linked to poorer responses to immune checkpoint inhibitors, making MDSCs an increasingly important part of the conversation around immunotherapy resistance.

As cancer treatment becomes more dependent on activating the immune system, understanding how MDSCs develop, how they suppress immunity, and whether they can be therapeutically targeted is becoming increasingly relevant to modern immuno-oncology.

What Are Myeloid-Derived Suppressor Cells (MDSCs) in Cancer?

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of pathologically activated myeloid cells with potent immunosuppressive activity. They expand during cancer and other chronic inflammatory conditions as normal myeloid development becomes disrupted. (Gabrilovich, 2017; Veglia et al., 2021).

Within the tumor microenvironment, MDSCs suppress T cells, natural killer cells, and other components of antitumor immunity. Through these effects, they create conditions that allow cancer cells to survive and avoid immune destruction. (Groth et al., 2019; Veglia et al., 2021).

Two major populations are recognized: polymorphonuclear MDSCs (PMN-MDSCs), which are closely related to neutrophils, and monocytic MDSCs (M-MDSCs), which resemble monocytes. Their phenotype and suppressive mechanisms can differ depending on the tumor and surrounding microenvironment. (Veglia et al., 2021; Deng et al., 2026).

MDSCs have become particularly important in cancer immunology because their accumulation is associated with tumor progression, immune escape, and reduced responses to several forms of immunotherapy.

How Do MDSCs Develop and Accumulate in the Tumor Microenvironment?

Cancer alters normal myeloid development through persistent inflammatory and tumor-derived signals. These signals can expand immature myeloid precursors, interfere with normal differentiation, and promote pathological activation of neutrophil- and monocyte-lineage cells. (Veglia et al., 2021; Deng et al., 2026).

Tumor and stromal cells release factors such as G-CSF, GM-CSF, IL-6, IL-1β, VEGF, and prostaglandin E2, activating pathways including STAT3, STAT5, NF-κB, and C/EBPβ. Together, these signals promote the expansion and suppressive activity of MDSCs. (Groth et al., 2019; Deng et al., 2026).

MDSCs are then recruited toward tumors through chemokine pathways. CCL2–CCR2 is particularly important for M-MDSCs, while CXCL5/CXCL8–CXCR2 signaling contributes to PMN-MDSC recruitment. Other pathways, including CCL5–CCR5 and CXCL12–CXCR4, can also participate. (Deng et al., 2026).

Once inside the tumor, hypoxia, inflammatory signals, metabolic stress, and tumor-derived factors further reinforce their suppressive phenotype.

How Do MDSCs Suppress T Cells and Antitumor Immunity?

MDSCs suppress antitumor immunity through several complementary mechanisms.

One important pathway is nutrient depletion. Arginase-1 reduces local L-arginine availability, impairing T-cell proliferation and receptor signaling. Some MDSCs can also alter tryptophan metabolism through indoleamine 2,3-dioxygenase, further limiting T-cell activity. (Kumar et al., 2016; Veglia et al., 2021).

MDSCs also generate reactive oxygen and nitrogen species, which can interfere with T-cell receptor signaling and contribute to T-cell dysfunction. (Ostrand-Rosenberg and Fenselau, 2018; Groth et al., 2019).

They can additionally express PD-L1 and release immunosuppressive cytokines such as IL-10 and TGF-β. These signals suppress effector T cells, promote regulatory T-cell activity, and reinforce an immunosuppressive tumor environment. (Veglia et al., 2021).

MDSCs can also interfere with lymphocyte trafficking, antigen presentation, and NK-cell activity. Together, these mechanisms weaken both innate and adaptive antitumor immunity.

How Do MDSCs Cause Resistance to Immune Checkpoint Inhibitors?

Immune checkpoint inhibitors release inhibitory signals such as PD-1, PD-L1, and CTLA-4, but they still depend on functional antitumor immune cells being present within the tumor.

MDSCs create a parallel layer of immune suppression that checkpoint blockade does not automatically remove. Even when PD-1 or CTLA-4 signaling is inhibited, an MDSC-rich tumor microenvironment may still restrict T-cell infiltration, activation, metabolism, and survival. (Weber et al., 2018; Li X et al., 2021).

MDSCs can also promote abnormal angiogenesis, hypoxia, and metabolic stress, further limiting effective immune-cell activity within the tumor. As a result, they can contribute to a poorly inflamed or immunologically resistant tumor microenvironment.

Clinical studies and meta-analyses have associated higher circulating MDSC levels with poorer outcomes during immune checkpoint inhibitor therapy, although MDSCs are only one of several mechanisms of primary and acquired immunotherapy resistance. (Li K et al., 2021; Deng et al., 2026).

This has made MDSCs an important target in efforts to overcome resistance to checkpoint blockade.

Which Cancers Have High Levels of MDSCs?

MDSCs have been identified across many cancers and are particularly prominent in advanced and metastatic solid tumors.

Elevated circulating or tumor-associated MDSCs have been reported in lung, breast, colorectal, gastric, esophageal, pancreatic, liver, renal, ovarian, prostate, bladder, and head and neck cancers, as well as melanoma. They are also found in several hematologic malignancies. (Veglia et al., 2021; Deng et al., 2026).

The relative abundance of PMN-MDSCs and M-MDSCs varies between tumor types, disease stages, and individual patients. Differences in laboratory definitions and flow-cytometry markers also make direct comparisons between studies difficult.

Higher MDSC levels have repeatedly been associated with advanced disease and poorer survival. For example, increased circulating MDSCs were independently associated with worse outcomes in patients with pancreatic, esophageal, and gastric cancers, while a broader meta-analysis across solid tumors also found an adverse prognostic association. (Gabitass et al., 2011; Zhang et al., 2016).

Despite this, MDSC measurement is not yet standardized enough to serve as a universal clinical biomarker.

Can MDSCs Be Targeted to Improve Immunotherapy Response?

MDSCs are increasingly being explored as therapeutic targets, particularly as a way to improve the effectiveness of immunotherapy.

Current strategies generally fall into four categories: reducing MDSC numbers, blocking their recruitment, inhibiting their suppressive functions, or promoting differentiation into less suppressive myeloid cells. (Law et al., 2020; Deng et al., 2026).

Blocking pathways such as CXCR2/CXCL and CCR2/CCL2 may reduce MDSC recruitment into tumors. Other approaches target suppressive mechanisms including arginase activity, nitric oxide signaling, and related metabolic pathways. Agents such as all-trans retinoic acid have also been studied as a way to promote myeloid differentiation. (Law et al., 2020; Li K et al., 2021).

Combining MDSC-directed strategies with PD-1, PD-L1, or CTLA-4 inhibitors is particularly attractive because it targets both checkpoint signaling and the suppressive myeloid environment. Preclinical studies have repeatedly shown improved T-cell infiltration and tumor control with such combinations. (Li X et al., 2021).

Clinical translation, however, remains challenging. MDSCs are highly heterogeneous, many of the pathways being targeted are shared with normal myeloid cells, and several promising preclinical strategies have produced limited or inconsistent clinical benefit. (Deng et al., 2026).

MDSCs may represent one of the missing pieces in immunotherapy resistance: even when checkpoint inhibition releases the brakes on T cells, a suppressive myeloid environment can still prevent those cells from functioning effectively.