The tumor microenvironment is not only composed of cancer cells but also includes a complex network of immune, stromal, and endothelial cells that actively influence tumor progression. Among immune populations, myeloid-derived suppressor cells (MDSCs) play a central role in shaping an immunosuppressive environment that allows tumors to evade immune surveillance.
MDSCs are a heterogeneous population of immature myeloid cells that expand during cancer, chronic infection, and inflammation. Their defining feature is their potent ability to suppress antitumor immune responses, particularly T cell–mediated cytotoxicity. By inhibiting immune effector cells and promoting regulatory pathways, MDSCs contribute to tumor growth, metastasis, and resistance to therapy.
In this article, we will examine how MDSCs originate and expand in cancer, how they are classified into distinct subtypes, the molecular mechanisms they use to suppress immune responses, their interactions with other components of the tumor microenvironment, and current strategies aimed at therapeutically targeting these cells.
Origin and Expansion of MDSCs in Cancer
Normal Myelopoiesis vs Pathological Myelopoiesis
Under physiological conditions, hematopoietic stem cells in the bone marrow differentiate into mature myeloid cells such as monocytes, macrophages, dendritic cells, and granulocytes. This process, known as myelopoiesis, is tightly regulated by growth factors and cytokines to ensure balanced immune function.
In cancer, this differentiation program becomes dysregulated. Persistent inflammatory signals and tumor-derived factors interfere with normal maturation, leading to the accumulation of immature myeloid cells with suppressive functions, which are classified as MDSCs. Instead of differentiating into antigen-presenting or phagocytic cells, these immature cells retain an immunosuppressive phenotype and are actively recruited to tumor sites.
This phenomenon is often referred to as pathological or emergency myelopoiesis, reflecting a systemic shift in hematopoietic output toward suppressive cell populations.
Tumor-Derived Factors Driving MDSC Expansion
Tumors actively promote MDSC accumulation by secreting a broad range of soluble mediators that stimulate both proliferation and functional activation of these cells.
Key factors include:
- Growth factors
- Granulocyte-macrophage colony-stimulating factor (GM-CSF)
- Granulocyte colony-stimulating factor (G-CSF)
- Macrophage colony-stimulating factor (M-CSF)
- Inflammatory cytokines
- Interleukin-6 (IL-6)
- Interleukin-1β (IL-1β)
- Transforming growth factor-β (TGF-β)
These mediators activate intracellular signaling pathways in myeloid progenitors, particularly:
- STAT3 signaling, which promotes survival, proliferation, and inhibition of differentiation
- NF-κB signaling, which enhances inflammatory and suppressive gene expression
Sustained activation of these pathways locks myeloid cells into an immature, suppressive state, facilitating long-term MDSC accumulation in both circulation and tumor tissue.
Systemic vs Tumor-Localized MDSC Accumulation
MDSC expansion occurs at multiple anatomical levels:
- Bone marrow and spleen
- Increased production of immature myeloid cells
- Splenic extramedullary hematopoiesis in advanced cancer
- Peripheral blood
- Elevated circulating MDSC levels correlate with poor prognosis
- Tumor microenvironment
- Active recruitment via chemokine gradients
Chemokines involved in MDSC recruitment include:
- CXCL12 → CXCR4 axis
- CCL2 → CCR2 axis
- CCL5 → CCR5 axis
Once within the tumor, hypoxia, metabolic stress, and cytokine exposure further enhance MDSC suppressive activity, making them more potent inhibitors of local immune responses.
Major Subtypes and Phenotypic Markers of MDSCs
MDSCs are not a single uniform cell type but rather a heterogeneous group of immature myeloid cells that share suppressive activity but differ in morphology, surface markers, and mechanisms of immune regulation. They are broadly classified into two major subtypes based on their resemblance to normal myeloid lineages.
Monocytic MDSCs (M-MDSCs)
Monocytic MDSCs are morphologically and phenotypically similar to monocytes but are functionally distinct due to their strong immunosuppressive properties.
Phenotypic characteristics:
- In mice: CD11b⁺ Ly6C^high Ly6G⁻
- In humans: CD11b⁺ CD14⁺ HLA-DR^low/− CD15⁻
Functional features:
- High production of:
- Nitric oxide (NO) via inducible nitric oxide synthase (iNOS)
- Immunosuppressive cytokines such as IL-10 and TGF-β
- Strong inhibition of:
- CD8⁺ cytotoxic T lymphocyte activity
- Antigen presentation by dendritic cells
M-MDSCs are highly plastic and can further differentiate within the tumor microenvironment into:
- Tumor-associated macrophages (TAMs) with M2-like phenotypes
- Immunosuppressive dendritic-like cells
This differentiation capacity allows M-MDSCs to act as precursors of other suppressive populations, reinforcing long-term immune suppression within tumors.
Polymorphonuclear MDSCs (PMN-MDSCs)
Polymorphonuclear MDSCs resemble neutrophils in both morphology and surface marker expression but differ in transcriptional programs and suppressive activity.
Phenotypic characteristics:
- In mice: CD11b⁺ Ly6G⁺ Ly6C^low
- In humans: CD11b⁺ CD15⁺ CD14⁻ LOX-1⁺ (proposed marker)
Functional features:
- Dominant production of:
- Reactive oxygen species (ROS)
- Peroxynitrite
- Preferential suppression of:
- T cell receptor signaling
- Antigen-specific T cell responses
PMN-MDSCs are often the most abundant MDSC population in peripheral blood, especially in advanced-stage cancers. Their short lifespan is compensated by continuous replenishment from pathological myelopoiesis driven by tumor-derived factors.
Challenges in MDSC Identification
One of the major obstacles in both research and clinical application is the difficulty in accurately distinguishing MDSCs from normal myeloid cells, especially neutrophils and monocytes.
Key challenges include:
- Overlapping surface markers with normal immune cells
- Lack of universally accepted markers in humans
- Functional definition required for true identification
As a result, many studies define MDSCs using a combination of:
- Surface marker panels
- Functional suppression assays
- Transcriptomic or metabolic signatures
Recently, metabolic features such as increased fatty acid uptake and altered mitochondrial activity have been proposed as additional discriminatory characteristics, suggesting that functional metabolism-based profiling may improve MDSC detection in the future.
Mechanisms of Immune Suppression by MDSCs
The defining characteristic of MDSCs is their strong capacity to suppress antitumor immune responses. They inhibit multiple immune cell types simultaneously and use metabolic, biochemical, and signaling-based mechanisms to create a deeply immunosuppressive tumor microenvironment.
Inhibition of T Cell Activation and Proliferation
T lymphocytes are primary targets of MDSC-mediated suppression. MDSCs interfere with both T cell activation and clonal expansion, which are essential for effective antitumor immunity.
Key mechanisms include:
- L-arginine depletion
- MDSCs express high levels of arginase-1 (ARG1)
- Degradation of L-arginine reduces CD3ζ-chain expression in T cells
- This impairs T cell receptor (TCR) signaling and cell cycle progression
- Nitric oxide (NO) production
- Induced by iNOS in M-MDSCs
- NO inhibits IL-2 signaling and promotes T cell apoptosis
- Also interferes with antigen presentation machinery
- Reactive oxygen and nitrogen species (ROS/RNS)
- Predominantly produced by PMN-MDSCs
- Cause nitration of TCR and MHC molecules
- Reduce antigen-specific T cell recognition
These combined effects result in functional paralysis of effector T cells, even in the presence of tumor antigens.
Induction of Regulatory Immune Cells
Beyond direct inhibition, MDSCs actively reshape immune populations toward suppressive phenotypes.
They promote:
- Expansion of regulatory T cells (Tregs)
- Through secretion of IL-10 and TGF-β
- Via antigen presentation under tolerogenic conditions
- Suppression of dendritic cell maturation
- Reduced expression of costimulatory molecules (CD80, CD86)
- Impaired antigen presentation to naïve T cells
- Inhibition of natural killer (NK) cell cytotoxicity
- Reduced perforin and granzyme production
- Decreased expression of activating receptors
This shifts the immune balance from tumor elimination toward immune tolerance, reinforcing long-term immune escape.
Metabolic and Epigenetic Regulation of Immunity
MDSCs also suppress immunity by altering the metabolic landscape of the tumor microenvironment.
Key metabolic effects include:
- Competition for nutrients
- Consumption of glucose and amino acids
- Limits resources needed for T cell proliferation
- Production of immunosuppressive metabolites
- Adenosine accumulation
- Kynurenine from tryptophan metabolism via IDO pathways
- Lipid metabolism reprogramming
- Increased fatty acid uptake enhances suppressive capacity
- Supports mitochondrial oxidative metabolism in MDSCs
In addition, MDSCs influence immune responses through epigenetic mechanisms, including:
- Histone modifications regulating cytokine expression
- MicroRNA-mediated control of immune signaling pathways
These changes stabilize suppressive phenotypes and allow MDSCs to adapt dynamically to different tumor microenvironments.
Interaction of MDSCs with Other TME Components
MDSCs do not act in isolation within tumors. Instead, they engage in extensive bidirectional communication with stromal, immune, and endothelial cells, forming cooperative networks that sustain tumor growth and immune suppression. These interactions amplify the overall suppressive capacity of the tumor microenvironment and promote structural remodeling that facilitates invasion and metastasis.
Crosstalk with Cancer-Associated Fibroblasts (CAFs)
Cancer-associated fibroblasts are major producers of cytokines, chemokines, and extracellular matrix components that regulate immune cell behavior.
Key CAF–MDSC interactions include:
- CAF-driven recruitment and survival of MDSCs
- Secretion of CXCL12, IL-6, and GM-CSF promotes MDSC trafficking and persistence
- Activation of STAT3 signaling in MDSCs enhances suppressive gene expression
- Reciprocal activation loops
- MDSCs release TGF-β and matrix metalloproteinases (MMPs)
- These factors further activate fibroblasts and stimulate ECM remodeling
This feedback loop stabilizes a fibrotic, immune-excluded tumor phenotype that limits immune cell infiltration and drug penetration.
Cooperation with Tumor-Associated Macrophages (TAMs)
MDSCs and TAMs represent overlapping and interconnected suppressive myeloid populations.
Important interactions include:
- Differentiation of M-MDSCs into TAMs
- Driven by tumor-derived cytokines and hypoxia
- Results in accumulation of M2-like macrophages
- Shared suppressive signaling pathways
- IL-10, TGF-β, and STAT3-mediated transcription programs
- Coordinated suppression of cytotoxic T lymphocytes
- Joint promotion of angiogenesis
- Production of VEGF, PDGF, and pro-angiogenic chemokines
- Supports abnormal vascular networks characteristic of tumors
Together, MDSCs and TAMs establish a dominant myeloid-driven suppressive axis that is strongly associated with poor clinical outcomes.
Role in Angiogenesis and ECM Remodeling
Beyond immune suppression, MDSCs actively contribute to the structural evolution of tumors.
Their pro-tumorigenic functions include:
- Angiogenic factor secretion
- VEGF, Bv8 (prokineticin 2), and angiopoietins
- Promote formation of leaky and disorganized blood vessels
- Matrix degradation
- Expression of MMP-2 and MMP-9
- Facilitates tumor cell invasion and intravasation
- Promotion of endothelial cell survival
- Protects tumor vasculature from therapy-induced damage
These processes enhance tumor perfusion while simultaneously creating physical and immunological barriers that limit effective immune infiltration and therapeutic delivery.
MDSCs in Tumor Progression, Metastasis, and Therapy Resistance
Beyond local immune suppression, MDSCs actively participate in multiple stages of cancer progression, including tumor growth, dissemination, and resistance to treatment. Their systemic effects make them key drivers of poor clinical outcomes.
Formation of Pre-Metastatic Niches
Before tumor cells arrive at distant organs, primary tumors can condition these sites to become supportive of future metastasis. MDSCs are major contributors to this process.
Key mechanisms include:
- Early accumulation in distant tissues
- Liver, lungs, bone marrow, and lymph nodes
- Recruited by tumor-derived factors and exosomes
- Extracellular matrix remodeling
- Deposition of fibronectin
- Increased MMP activity facilitating cell invasion
- Immune suppression at secondary sites
- Inhibition of resident immune surveillance
- Promotion of local tolerance to incoming tumor cells
These changes create a pre-metastatic niche that enhances survival and colonization of circulating tumor cells (CTCs).
Support of Circulating Tumor Cells and Extravasation
MDSCs can directly assist tumor cells during dissemination through the bloodstream.
They contribute by:
- Forming heterotypic clusters with tumor cells
- Physical protection from immune-mediated destruction
- Increased resistance to shear stress
- Enhancing endothelial permeability
- Through cytokines and VEGF signaling
- Facilitates tumor cell extravasation into tissues
- Secreting survival-promoting factors
- Supports early metastatic outgrowth
Thus, MDSCs are not only passive immune regulators but also active facilitators of metastatic spread.
Contribution to Resistance to Immunotherapy
High levels of MDSCs are consistently associated with poor response to immune checkpoint inhibitors and other immune-based therapies.
Mechanisms of resistance include:
- Suppression of reinvigorated T cells after checkpoint blockade
- Maintenance of immunosuppressive cytokine networks
- Metabolic inhibition of immune cell function within tumors
Clinically, increased circulating MDSCs often correlate with:
- Reduced overall survival
- Lower objective response rates to immunotherapy
This has led to growing interest in using MDSC frequency as a predictive biomarker for patient stratification.
Impact on Chemotherapy and Targeted Therapy Outcomes
Conventional anticancer therapies can paradoxically increase MDSC levels.
Observed effects include:
- Therapy-induced inflammation
- Leads to compensatory myelopoiesis
- Increases MDSC recruitment after treatment
- Protection of tumor cells
- MDSC-derived cytokines activate survival pathways
- Promote tumor cell dormancy and relapse
- Reduced drug penetration
- Due to vascular abnormalities and fibrosis promoted by MDSCs
As a result, MDSCs contribute to minimal residual disease and tumor recurrence, even after initial therapeutic responses.
Therapeutic Targeting of MDSCs
Given their central role in immune suppression and therapy resistance, MDSCs have become an important target in modern cancer therapy. Current strategies aim not only to eliminate MDSCs but also to block their recruitment, inhibit their suppressive mechanisms, or reprogram them into non-suppressive cells, often in combination with immunotherapies.
Strategies to Deplete MDSCs
Several conventional and targeted agents can reduce MDSC abundance, either directly or indirectly.
Approaches include:
- Low-dose chemotherapeutic agents
- Selectively reduce proliferating MDSCs
- Can enhance antitumor immune responses when properly timed
- Targeting growth factor signaling
- Inhibition of GM-CSF or G-CSF pathways
- Reduces pathological myelopoiesis
- Antibody-mediated depletion
- Directed against surface markers enriched on MDSC subsets
- More commonly explored in preclinical models
However, systemic depletion of myeloid cells carries the risk of compromising normal immune defense, making selectivity and dosing critical factors.
Blocking MDSC Recruitment and Suppressive Function
Rather than eliminating MDSCs, many strategies aim to prevent their accumulation in tumors or neutralize their inhibitory mechanisms.
Key targets include:
- Chemokine receptors
- CCR2, CCR5, and CXCR2 antagonists block trafficking to tumors
- Metabolic enzymes
- Arginase inhibitors restore L-arginine availability
- iNOS inhibitors reduce nitric oxide–mediated suppression
- Adenosine signaling pathways
- Inhibition of adenosine receptors improves immune activation
These approaches are particularly effective when combined with immune checkpoint blockade, as they help convert non-responsive tumors into immune-permissive environments.
Reprogramming MDSCs into Immune-Activating Cells
An emerging concept in cancer therapy is the functional reprogramming of suppressive myeloid cells rather than their elimination.
Reprogramming strategies include:
- Differentiation therapy
- Promotes maturation into macrophages or dendritic cells
- Restores antigen presentation capacity
- Epigenetic modulators
- Alter transcriptional programs supporting suppression
- Innate immune stimulators
- Activate pattern-recognition receptors to shift immune phenotype
These methods aim to transform MDSCs from tumor-supporting cells into participants in antitumor immunity, offering a potentially safer and more durable therapeutic strategy.
Conclusion
Myeloid-derived suppressor cells represent one of the most powerful immunosuppressive forces within the tumor microenvironment. By inhibiting effector immune cells, promoting regulatory networks, remodeling tissue architecture, and facilitating metastasis, MDSCs contribute at every stage of cancer progression and significantly limit therapeutic success.
Understanding the origin, heterogeneity, and functional mechanisms of MDSCs has revealed multiple opportunities for therapeutic intervention. Strategies that target MDSCs — particularly in combination with immunotherapies — are increasingly recognized as essential for overcoming resistance and improving long-term clinical outcomes.
As research continues to uncover the molecular and metabolic regulation of these cells, MDSCs are likely to remain a central focus in efforts to convert immunologically “cold” tumors into responsive, immune-active environments.
