The tumor microenvironment in hematologic malignancies: immune evasion, metabolic reprogramming, and therapeutic resistance

Abstract

Hematological malignancies, including leukemia, lymphoma, and multiple myeloma, develop within and remain dependent on a complex and dynamic tumor microenvironment (TME). Malignant cells interact continuously with the cellular and molecular components of the TME, which play a critical role in shaping disease progression, therapeutic response, and immune evasion. The TME comprises mesenchymal stromal cells, immune cells, fibroblasts, endothelial cells, and a range of signaling molecules such as chemokines, cytokines, and extracellular vesicles, embedded within a heterogeneous extracellular matrix (ECM). This integrated network, along with recently established mechanisms, establishes a supportive niche that promotes malignant cell survival, clonal evolution, immune modulation, and therapy resistance. This review examines the cellular and molecular architecture of the hematologic TME and its influence on chemoresistance and immune suppression. It further discusses therapeutic interventions that aim to disrupt or reprogram the TME, thereby restoring therapeutic sensitivity and enhancing immune-mediated clearance.

1. INTRODUCTION

Hematological malignancies comprise a heterogeneous group of neoplasms involving the blood, bone marrow, and lymphoid tissues.¹ Each category includes multiple biologically distinct subtypes. These malignancies fall into 3 major classifications: leukemia, lymphoma, and plasma cell neoplasms. Leukemia originates from the clonal expansion of immature hematopoietic progenitors (blasts) in the bone marrow. These cells infiltrate the peripheral blood and lymphoid tissues.² It is subdivided based on the onset of the disease, that is, acute or chronic, and the lineage involved, myeloid or lymphoid. Lymphoma arises from malignant transformation of lymphocytes, predominantly B-cells or T-cells, and less frequently natural killer (NK) cells. It typically presents in lymphoid tissues but may involve extra nodal sites. The World Health Organization recognizes more than 90 distinct lymphoma subtypes, reflecting their genetic, phenotypic, and clinical diversity.³ Multiple myeloma (MM), a member of plasma cell neoplasms, involves neoplastic proliferation of terminally differentiated B-cells or plasma cells. These clonal cells accumulate in the bone marrow and disrupt normal hematopoiesis. MM often causes lytic bone lesions, anemia, hypercalcemia, and renal impairment due to monoclonal protein production and marrow infiltration.^4,5

Recent studies show that hematological malignancies share common pathogenic mechanisms, particularly within the tumor microenvironment (TME). Traditional cancer research focused primarily on intrinsic tumor cell biology and molecular pathways, often overlooking the surrounding stromal and immune components. Emerging evidence has emphasized the role of the TME in regulating tumorigenesis, progression, and therapeutic outcomes.² The TME consists of diverse immune and stromal cells. These elements interact dynamically to promote malignant cell proliferation, immune evasion, therapy resistance, and metastasis. In hematologic neoplasms, the TME not only displays disease-specific variations but also exhibits overlapping mechanisms. Distinct factors contribute to each malignancy.⁶ In MM, ECM remodeling supports clonal expansion and drug resistance.^7–9

In chronic myeloid leukemia (CML), the bone marrow microenvironment supports malignant progenitors through chemokine gradients, stromal contact, and kinase-independent survival signals. These interactions contribute to minimal residual disease despite tyrosine-kinase inhibitor (TKI) therapy.^8,10 Studies also suggest the involvement of immunoregulatory myeloid cells and altered NK cell function in CML progression and relapse. In acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), the bone marrow niche acquires therapeutic resistance through defined cellular and molecular axes. AML blasts preferentially occupy hypoxic niches and are supported by mesenchymal stem cells (MSC)- and endothelial-derived C-X-C motif chemokine ligand (CXCL12) signaling.¹⁰ Tumor-associated macrophages (TAMs) and MDSCs are enriched in AML, where they produce interleukin (IL)-10, transforming growth factor-beta (TGF-β), and metabolic mediators that suppress T-cell responses. These features are associated with poor outcomes and relapse.^7,11,12 Moreover, increased fatty acid oxidation (FAO) creates pro-survival metabolic states in myeloid diseases.^13,14

This review highlights the cellular and non-cellular components of the TME across hematological malignancies. It explores their roles in neoplastic transformation, disease progression, treatment resistance, and immune modulation. Additionally, recent advances in TME-targeted therapeutic strategies are examined in the context of hematological malignancies.

2. OVERVIEW OF THE TME IN HEMATOLOGICAL MALIGNANCIES

The hematological TME exhibits distinct structural and functional features compared to that of solid tumors. In solid tumors, the TME is shaped by the surrounding tissue architecture governing several complex interactions. These interactions result in compartments that are spatially restricted and influenced by hypoxia, interstitial pressure, and ECM density. In contrast, the TME in hematological malignancies is more dynamic and spatially diffuse. It primarily resides within the bone marrow, lymph nodes, spleen, and other lymphoid tissues. Hematologic TME lacks the rigid compartmentalization seen in solid tumors, allowing continuous interaction between malignant cells and their microenvironmental components. This fluidity facilitates systemic dissemination, immune modulation, and therapeutic resistance.¹⁵ The bone marrow niche serves as a central component of TME in hematological malignancies. It provides the primary residence for adult hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). This specialized microenvironment comprises both cellular and non-cellular components. Malignant cells utilize this niche to support their survival, proliferation, and evasion from chemotherapy. The bone marrow TME facilitates leukemic cell adhesion, metabolic adaptation, immune suppression, and resistance to apoptosis. These interactions contribute to minimal residual disease and relapse following treatment.¹⁶ The interactions of various stromal and immune cells to promote tumor progression in hematological malignancies are illustrated in Figure 1.

Figure 1.

Cellular and molecular interactions within the tumor microenvironment in hematological malignancies. Mesenchymal stromal cells, fibroblasts, cancer-associated fibroblasts, endothelial cells, and various immune cells interact to promote tumor progression. Key processes depicted include cytokine secretion, extracellular matrix remodeling, angiogenesis, immune suppression, and the survival of malignant cells. Arrows indicate the direction of cellular interactions and signaling pathways involved in these processes. α-SMA = α-smooth muscle actin, Arg-1 = arginase-1, DC = dendritic cells, FAP = fibroblast activation protein, IL = interleukin, iNOS = inducible nitric oxide synthase, MDSC = myeloid-derived suppressor cell, MMPs = metalloproteinases, NK = natural killer, PD-1 = programmed death-1, PD-L1 = programmed death-ligand 1, ROS = reactive oxygen species, TAM = tumor-associated macrophage, TGF-β = transforming growth factor-beta, Tregs = regulatory T cells, VEGF = vascular endothelial growth factor.

3. CELLULAR COMPONENTS OF THE HEMATOLOGIC TME

3.1. Mesenchymal stromal cells

The bone marrow microenvironment includes a structured network of MSCs, also known as bone marrow stromal cells (BMSCs). MSCs are multipotent precursor cells capable of self-renewal and differentiation into osteoblasts, chondrocytes, and adipocytes.¹⁷ Within the TME of hematological malignancies, MSCs contribute to tumor progression through interactions with malignant hematopoietic cells and immune effectors. These interactions modulate local immune responses and establish an immunosuppressive niche that enables malignant cells to escape immune surveillance. Leukemic MSCs support leukemic stem cell (LSC) survival and proliferation by secreting soluble factors, including IL-8 and TGF-β. These cytokines enhance LSC self-renewal capacity and confer resistance to chemotherapy.¹⁸ Furthermore, MSCs influence immune cell trafficking within the TME. They suppress cytotoxic T cell activity by inducing T cell anergy and upregulating IL-10. This process impairs anti-tumor immunity and promotes the expansion of immunosuppressive populations, such as regulatory T cells (Tregs).¹⁹ Furthermore, MSCs also contribute to ECM remodeling by producing matrix metalloproteinases (MMPs) and other ECM-modifying enzymes. These enzymes degrade matrix components, facilitate tumor cell migration, and promote tissue invasion, thereby accelerating disease progression.²⁰ MSCs also influence vascular architecture. They can differentiate into pericytes or endothelial-like cells, integrating into the vascular niche. Alternatively, they secrete pro-angiogenic factors such as vascular endothelial growth factor (VEGF), which modulate neovascularization and sustain tumor growth.²¹ The role of MSCs in hematological malignancies extends well beyond structural support. MSCs suppress anti-tumor immune responses, promote angiogenic remodeling, and sustain leukemic cell survival through paracrine signaling and direct cell-cell interactions. These functions contribute to clonal expansion, immune evasion, and resistance to chemotherapeutic agents. By adopting these microenvironmental changes, MSCs establish a permissive and protective niche that facilitates malignant progression and therapeutic failure. Clinically, MSC-driven secretion of cytokines and chemokines correlates with minimal residual disease and reduced chemotherapy sensitivity in AML and MM, supporting CXCR4/IL-6 pathway-directed clinical interventions.^22,23

3.2. Fibroblasts

Fibroblasts are essential stromal components of the hematologic TME and contribute significantly to disease progression in leukemia, lymphoma, and MM.²⁴ Under pathological stimuli, fibroblasts differentiate into cancer-associated fibroblasts (CAFs). They acquire an activated phenotype characterized by upregulated expression of α-smooth muscle actin (α-SMA), fibroblast activation protein (FAP), and enhanced secretion of pro-tumorigenic cytokines and growth factors.²⁵ These activated fibroblasts establish a supportive and immunosuppressive niche that facilitates malignant cell proliferation, survival, and therapy resistance. CAFs participate actively in ECM remodeling through the secretion of structural proteins such as collagen and fibronectin, along with matrix-modifying enzymes, including MMPs.²⁶ These alterations modulate the mechanical properties of the bone marrow microenvironment, leading to increased tissue stiffness and formation of a protective scaffold that protects malignant hematopoietic cells from therapeutic agents.²⁷ In MM, CAFs contribute to fibronectin accumulation, promoting cell adhesion-mediated drug resistance and limiting the efficacy of proteasome inhibitors.²⁴

In addition to structural remodeling, CAFs release several immunomodulatory factors such as TGF-β and CXCL12. These mediators impair anti-tumor immune responses, promote the recruitment of Tregs and myeloid-derived suppressor cells (MDSCs), and suppress cytotoxic T cell function, thereby enabling immune evasion and malignant expansion.²⁸ CAFs also contribute to tumor angiogenesis. By interacting with endothelial cells and secreting proangiogenic molecules such as VEGF and fibroblast growth factor (FGF), they support the formation of aberrant vasculature that sustains tumor growth and dissemination.²⁹ Therapy resistance mediated by CAFs has been well characterized in several hematological malignancies. In chronic lymphocytic leukemia (CLL), fibroblasts protect leukemic cells from apoptosis by activating survival pathways, including Bcl-2 and phosphoinositide 3-kinase (PI3K)/Akt signaling cascades.³⁰ Similarly, in AML, CAFs enhance chemoresistance by providing metabolic substrates that support oxidative phosphorylation in LSCs, thereby enabling persistence under cytotoxic stress.³¹ Given their diverse roles in immune modulation, metabolic support, ECM remodeling, and angiogenesis, fibroblasts, particularly CAFs, represent a promising therapeutic target in hematologic cancers. Strategies aimed at disrupting fibroblast-tumor interactions or reversing CAF activation are under investigation and may enhance treatment response and overcome resistance.³⁰

3.3. Endothelial cells

Endothelial cells are integral components of the hematologic TME, primarily regulating angiogenesis, vascular permeability, and immune cell trafficking.³² A hallmark feature of endothelial cells in hematologic malignancies is tumor-induced angiogenesis. In contrast to solid tumors, where angiogenesis supports tumor mass expansion, the abnormal neovascularization observed in the bone marrow and lymphoid organs enhances malignant cell survival and proliferation without forming discrete tumor masses.³³ Malignant hematopoietic cells secrete pro-angiogenic factors, including VEGF, FGF, and angiopoietins, which stimulate endothelial cell proliferation and pathological vessel formation.³⁴ This establishes a reciprocal feedback loop wherein endothelial cells support malignant hematopoiesis, and malignant cells continuously promote endothelial activation and expansion.

In addition, leukemic cells can induce endothelial-to-mesenchymal transition (EndMT), a process whereby endothelial cells lose their vascular identity and acquire a mesenchymal, fibroblast-like phenotype with pro-tumorigenic properties.³⁵ EndMT contributes to ECM remodeling and enhances the formation of a supportive leukemic niche.³⁶

The bone marrow vasculature in hematologic malignancies is structurally and functionally abnormal. It exhibits increased permeability, irregular branching, and altered perfusion.³⁷ This is primarily due to VEGF-induced vascular leakage, facilitating the egress of leukemic cells into the circulation and promoting dissemination.³⁸ Tumor-derived extracellular vesicles (EVs) and soluble factors can exit through this leaky vasculature and modify distant microenvironments, preparing pre-metastatic niches for disease dissemination.³⁹

Beyond angiogenesis, endothelial cells modulate immune responses within the TME. They contribute to immune evasion by modulating CD8⁺ T cells to produce immunosuppressive cytokines such as IL-10 and TGF-β, thereby reducing effective anti-tumor immunity.⁴⁰ This is primarily based on correlative evidence in patient samples, with mechanistic confirmation still limited. Furthermore, endothelial cells participate in therapy resistance by activating anti-apoptotic signaling pathways in malignant cells. In MM, they release cytokines that protect tumor cells from chemotherapeutic stress and reduce treatment efficacy.⁴¹

3.4. Immune cells

Immune cells are integral components of the hematologic TME and play pivotal roles in supporting disease progression, modulating immune surveillance, and influencing therapeutic outcomes. Although the immune system is inherently designed to recognize and eliminate malignant cells, hematologic malignant neoplasms develop mechanisms that disrupt immune homeostasis. Malignant cells alter the metabolism, function, distribution, or survival of immune effector populations, thereby establishing an immunosuppressive microenvironment that facilitates tumor persistence and immune evasion.⁴²

3.4.1. Macrophages and dendritic cells

TAMs represent a prominent bone marrow-derived myeloid cell population within the hematologic TME. These macrophages often acquire an M2-like phenotype, characterized by immunosuppressive, pro-angiogenic, and tumor-promoting functions.⁴³ In MM and other hematologic malignancies, M2-polarized macrophages secrete IL-10 and TGF-β, which inhibit cytotoxic T-cell activity and enhance malignant cell survival.⁴⁴ High TAM density and an M2-like phenotype correlate with poorer overall survival and therapeutic resistance in MM and certain lymphomas.⁴⁵ TAM-derived cytokines also interfere with the function of dendritic cells (DC). Elevated levels of TGF-β and VEGF impair DC maturation, reduce the expression of chemokine receptors such as CCR7, and downregulate DEC205, a key receptor involved in DCs’ antigen uptake and presentation. These changes compromise DC migratory capacity to TME and antigen-presenting function, which exacerbates the defective T-cell priming and facilitates immune evasion.¹¹

3.4.2. MDSCs and neutrophils

MDSCs are a heterogeneous population of immature myeloid cells that accumulate within the TME and exert potent immunosuppressive effects. They are broadly categorized into 2 major subsets: polymorphonuclear MDSCs (PMN-MDSCs), which phenotypically resemble neutrophils, and monocytic MDSCs (M-MDSCs), which resemble monocytes.⁴⁶ MDSCs promote tumor immune evasion through multiple mechanisms. They produce immunoregulatory enzymes such as arginase-1 (Arg1) and inducible nitric oxide synthase (iNOS), along with reactive oxygen species (ROS) and anti-inflammatory cytokines, including IL-10. These factors inhibit T-cell receptor signaling, suppress cytotoxic T-cell proliferation, and impair antigen-specific immune responses, thereby facilitating malignant cell survival and expansion.^46,47

Neutrophils also play dual roles in the TME and exhibit functional plasticity. They can polarize into either an anti-tumor (N1) or pro-tumor (N2) phenotype.⁴⁸ N2 neutrophils closely resemble PMN-MDSCs in both function and surface markers. They contribute to tumor progression by suppressing CD8⁺ T-cell responses and enhancing angiogenesis through VEGF secretion.⁴⁹ In patients with CLL, neutrophils inhibit T-cell activation and support an immunosuppressive microenvironment.⁴⁸ A high neutrophil-to-lymphocyte ratio (NLR) has emerged as a negative prognostic marker in several hematologic malignancies, including MM and lymphoma. Elevated NLR reflects systemic inflammation and correlates with poor clinical outcomes, reduced overall survival, and impaired treatment response.⁵⁰

3.4.3. T cells: effector, regulatory, and exhausted T cells

T cells in the hematologic TME frequently exhibit functional dysregulation due to persistent antigenic stimulation and the presence of immunosuppressive mediators.⁵¹ Three major T-cell subsets, effector T cells, Tregs, and exhausted T cells, differentially contribute to tumor progression and immune evasion.⁵² Effector T cells, particularly CD8⁺ cytotoxic T lymphocytes (CTLs), are critical mediators of anti-tumor immunity. CTLs recognize TAMs via major histocompatibility complex (MHC) class I and eliminate malignant cells by releasing perforin, granzyme B, and interferon-gamma (IFN-γ).⁵³ In lymphomas, CTL activity is frequently suppressed or outcompeted by TME-derived immunosuppressive mechanisms, leading to ineffective tumor control.⁵⁴ CD4⁺ helper T cells also influence tumor immunity. In AML, the Th17 subset is often increased, while the Th1 subset is reduced, particularly in newly diagnosed patients, leading to a Th17-biased cytokine milieu that favors immune dysregulation and is associated with poor prognosis.⁵⁵ Tumor cells modulate the Th1/Th17 ratio to shift immune responses toward a tolerogenic state, thereby contributing to an immunosuppressive environment in AML.

Tregs, defined by the expression of CD4⁺, CD25⁺, and FOXP3, suppress effector T-cell responses and maintain an immunosuppressive TME.⁵⁶ The aforementioned various conditions favor increased Treg numbers in the TME by promoting an anti-inflammatory environment in the TME. They result in an inhibition of T-cell activation through engagement of inhibitory pathways, such as PD-1 and CTLA-4, and compete for IL-2, depriving effector T cells of essential survival signals.⁵⁷ Elevated Treg frequencies correlate with poor clinical outcomes and resistance to immunotherapy in CLL, MM, and various subtypes of lymphoma.⁵⁸

T-cell exhaustion arises from chronic antigen exposure and sustained immune activation. Exhausted T cells display a gradual loss of effector function, reduced proliferative capacity, and increased expression of inhibitory receptors such as PD-1, T-cell immunoglobulin and mucin structural domain-3 (TIM-3), and lymphocyte-activation gene 3 (LAG-3).⁵⁹ In Hodgkin disease, a high proportion of exhausted T cells contributes to immune evasion and limits the effectiveness of host anti-tumor responses.⁶⁰

3.4.4. B cells and their dual role

B cells serve critical functions in adaptive immunity through antibody production, antigen presentation, and modulation of T-cell responses. However, in the context of hematologic malignancies, B cells can acquire pro-tumorigenic functions, contributing to immune evasion and disease progression.⁶¹ Regulatory B cells (Bregs) promote tumor growth by secreting immunosuppressive cytokines such as IL-10, which inhibit effector T-cell activation and promote a tolerogenic immune microenvironment. These cells also modulate antigen-presenting capacity and suppress cytotoxic immune responses, thereby facilitating malignant cell persistence.

In B-cell CLL, the malignant B cells themselves contribute directly to immune dysregulation. They are associated with chronic antigenic stimulation and exhibit prolonged survival supported by signaling through B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL).⁶² These interactions activate downstream survival pathways and enhance leukemic cell resistance to apoptosis. Conversely, memory B cells and plasma cells may support anti-tumor immunity by producing tumor-specific antibodies, facilitating antigen clearance, and contributing to long-term immune surveillance. The functional polarization of B cells within the TME remains context-dependent and disease-specific.⁶¹

3.4.5. NK cells

NK cells are key effectors of innate immunity and contribute to tumor surveillance by directly eliminating malignant cells through the release of cytotoxic molecules such as perforin, granzyme B, and IFN-γ.⁶³ Their activity is tightly regulated by a balance between activating and inhibitory signals mediated through surface receptors.

In hematological malignancies, NK cell function is frequently impaired. This dysfunction arises from multiple mechanisms, including the downregulation of activating receptors (NKG2D, NKp30, NKp46), upregulation of inhibitory ligands on tumor cells, and suppression by immunoregulatory cells such as Tregs and MDSCs.⁶⁴ These changes lead to impaired NK cell cytotoxicity and reduced immune clearance of malignant clones.

In AML, LSCs often lack expression of NKG2D ligands, thereby evading NK cell-mediated recognition and cytolysis.⁶⁵ Furthermore, AML blasts express high levels of inhibitory molecules such as HLA-E and programmed death-ligand 1 (PD-L1), which interact with NK cell inhibitory receptors, including NKG2A and PD-1. These interactions suppress NK cell activation and effector function, contributing to immune evasion and disease persistence.⁶⁶ Cellular components of the hematologic TME and their functional roles are summarized in Table 1.

Table 1.

Cellular components of the hematologic TME and their functional roles.

Cell type	Key functions in TME	Mechanisms promoting malignancy	Therapeutic target/strategy
MSCs	Structural support, cytokine secretion, ECM remodeling, immunosuppression	IL-6, CXCL12, TGF-β secretion; exosome/EV release; support of LSC survival and drug resistance	Disruption of CXCL12/CXCR4 (Plerixafor), IL-6 blockade (Siltuximab)
CAFs	ECM production, angiogenesis, immunosuppression, ECM cross-linking (LOX activity)	Secretion of fibronectin, VEGF, TGF-β; promote Treg recruitment and immune evasion, ECM remodeling	LOX/MMP inhibition, VEGF blockade, immune reprogramming
TAMs	Immunosuppression, angiogenesis, leukemic support, promotion of tumor cell proliferation and survival	M2 polarization, IL-10, TGF-β secretion, phagocytosis inhibition via CD47-SIRPα axis	Macrophage reprogramming, CSF1R inhibition, CD47-SIRPα axis blockade
MDSCs	T-cell suppression, oxidative stress modulation, promotion of angiogenesis	Arg-1, ROS, IL-10 production; promote T-cell exhaustion, induction of Treg cells	iNOS/Arg-1 inhibitors, depletion agents, CXCR2 blockade
Tregs	Suppression of CTLs, DCs, and NK cell activity	IL-10, TGF-β secretion; IL-2 consumption; PD-1 pathway activation, expression of CTLA-4	Checkpoint inhibitors (PD-1, CTLA-4), low-dose cyclophosphamide
DCs	Antigen presentation, T-cell priming, cross-presentation of tumor antigens	Impaired maturation due to TGF-β, VEGF; downregulation of MHC-II and costimulatory molecules, induction of tolerogenic DC phenotype by TME factors	FLT3-L, GM-CSF stimulation, TLR agonists
NK	Cytotoxicity against tumor cells, cytokine production (IFN-γ)	Downregulation of NKG2D ligands, upregulation of HLA-E, PD-L1; NK cell exhaustion, shedding of NKG2D ligands by tumor cells	NKG2A/PD-1 blockade, cytokine activation (IL-15, IL-21), NK-CAR therapy
Endothelial cells	Angiogenesis, immune modulation, regulation of leukocyte trafficking	VEGF secretion, EndMT induction, expression of immunomodulatory molecules (eg, IL-6, PD-L1), expression of adhesion molecules (ICAM-1, VCAM-1)	Anti-VEGF therapies, Notch/Dll4 inhibitors, vascular normalization strategies
Leukemic B cells (in CLL)	Immune suppression, antigen presentation, modulation of T cell responses	Chronic BCR activation, BAFF/APRIL signaling, interaction with nurse-like cells, secretion of immunosuppressive cytokines (eg, IL-10)	BCR signaling inhibitors (Ibrutinib, Acalabrutinib), BAFF/APRIL axis inhibition, anti-CD20 antibodies (rituximab)

Arg-1 = arginase-1, BCR = B-cell receptor, CAF = cancer-associated fibroblasts, CAR = chimeric antigen receptor, CLL = chronic lymphocytic leukemia, CTL = cytotoxic T lymphocyte, CTLA-4 = cytotoxic T-lymphocyte-associated antigen-4, CXCL12 = C-X-C motif chemokine ligand, DC = dendritic cells, ECM = extracellular matrix, EV = extracellular vesicle, FLT3-L = FMS-like tyrosine kinase 3 ligand, GM-CSF = granulocyte-macrophage colony-stimulating factor, ICAM-1 = intercellular adhesion molecule-1, IFN-γ = interferon-gamma, IL = interleukin, iNOS = inducible nitric oxide synthase, LOX = lysyl oxidase, LSC = leukemic stem cell, MDSC = myeloid-derived suppressor cell, MHC = major histocompatibility complex, MMP = matrix metalloproteinase, MSC = mesenchymal stem cells, NK = natural killer, PD-1 = programmed death-1, PD-L1 = programmed death-ligand 1, ROS = reactive oxygen species, TAM = tumor-associated macrophage, TGF-β = transforming growth factor-beta, TLR = toll-like receptor, TME = tumor microenvironment, Tregs = regulatory T cells, VCAM-1 = vascular cell adhesion molecule-1, VEGF = vascular endothelial growth factor.

4. NON-CELLULAR COMPONENTS AND SIGNALING MOLECULES IN THE TME

4.1. Cytokines, chemokines, and growth factors

A complex network of cytokines, chemokines, and growth factors facilitates the hematologic TME that contributes to disease progression, immune evasion, and therapeutic resistance. Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and IL-1β establish a supportive microenvironment by enhancing malignant cell survival, proliferation, and resistance to apoptosis.⁸ In MM, BMSCs secrete IL-6, which plays a critical role in promoting tumor growth and chemoresistance.⁶⁷ It promotes malignant plasma cell proliferation, enhances resistance to apoptosis, and activates downstream pathways such as the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase (MAPK), and PI3K/Akt. This relationship is functionally validated in preclinical blockade studies (see Section 5). In CLL, CD38+ expression on leukemic cells contributes to IL-6 secretion and is linked to disease progression and poor prognosis through positively influencing the IL-6 signaling pathway.⁶⁸

Chemokines such as CXCL12 and CCL2 regulate the trafficking and localization of both malignant and immune cells. In CLL, elevated CXCL12 levels in the bone marrow microenvironment enhance leukemic cell retention and niche protection, a causal link confirmed by CXCR4 inhibition in experimental systems (discussed in Section 5.3).⁶⁹ CCL2 facilitates the recruitment of TAMs, which further secrete immunosuppressive mediators like IL-10, impairing cytotoxic immune responses and promoting tumor immune escape.⁷⁰

Key growth factors modulate the TME by regulating cellular proliferation, differentiation, and intercellular signaling. VEGF leads to pathological angiogenesis and supports leukemic expansion in AML and MM. Granulocyte colony-stimulating factor (G-CSF), though less frequently produced by hematologic tumors, accelerates disease progression in certain malignancies by promoting myeloid proliferation and enhancing tumor-supportive inflammation.⁸

4.2. Hypoxia and metabolic reprogramming

Metabolic changes in immune cells are a major player in modulating their function.⁷¹ Hypoxia is a common feature of the bone marrow and lymphoid microenvironments in hematologic malignancies. Hypoxia significantly contributes to tumor progression, therapeutic resistance, and immune evasion. Under hypoxic conditions, hypoxia-inducible factor-1 alpha (HIF-1α) becomes stabilized and transcriptionally active. HIF-1α regulates a broad array of genes involved in angiogenesis, metabolic adaptation, stem cell maintenance, and immune suppression.

In AML, LSCs localize preferentially to hypoxic bone marrow niches. Within this environment, HIF-1α enhances glycolytic flux and reduces oxidative metabolism, thereby minimizing ROS accumulation and allowing leukemic cells to evade chemotherapy-induced apoptosis.⁷² This hypoxia-driven adaptation supports stemness and drug resistance.

In addition to aerobic glycolysis, hematologic malignancies exhibit dysregulation of alternative metabolic pathways that support tumor growth, immune escape, and resistance to therapy.⁷³

Glutamine metabolism plays a central role in fueling anabolic processes, maintaining redox homeostasis, and supporting nucleotide and amino acid biosynthesis. In MM, malignant plasma cells display a marked dependency on glutamine as a carbon and nitrogen source. Glutaminase (GLS), the enzyme that catalyzes the conversion of glutamine to glutamate, is frequently upregulated, promoting tricarboxylic acid (TCA) cycle anaplerosis and generating NADPH to buffer oxidative stress.⁷⁴ Inhibition of GLS has demonstrated cytotoxic effects in MM models, particularly when combined with proteasome inhibitors or agents targeting mitochondrial metabolism.¹³

Similarly, in CLL, leukemic B cells exhibit elevated glutamine uptake and metabolism, which supports energy production and redox balance. Glutamine-derived α-ketoglutarate contributes to mitochondrial respiration and epigenetic regulation, while glutathione biosynthesis from glutamate enhances antioxidant defences against ROS-induced apoptosis.⁷⁵

Lipid metabolism is also reprogrammed in these malignancies. MM cells demonstrate increased uptake and oxidation of fatty acids through upregulation of fatty acid transporters and FAO enzymes. FAO increases mitochondrial respiration, ATP production, and resistance to metabolic stress, while also modulating immune evasion via production of immunosuppressive lipid mediators.¹³ Inhibiting FAO has been shown to restore sensitivity to chemotherapy and impair MM cell survival.⁷⁶ In CLL, fatty acid metabolism supports mitochondrial fitness and contributes to survival signaling under nutrient-limited conditions. Leukemic B cells also engage in lipid droplet accumulation and fatty acid synthesis, which are associated with disease progression and stromal-mediated protection in the lymphoid niche.⁷⁷ These metabolic dependencies are tightly regulated by TME-derived signals, including cytokine, hypoxia-induced factors, and cell–cell interactions. Targeting glutaminolysis, lipid oxidation, or associated regulators (mechanistic target of Rapamycin [mTOR], adinosine monophosphate-activated protein kinase [AMPK] pathway, or peroxisome proliferator-activated receptor [PPAR] signaling) presents a promising strategy to disrupt metabolic plasticity and overcome drug resistance in MM and CLL.⁷⁸

4.3. Extracellular vesicles

EVs, including exosomes (30–150 nm) and microvesicles (100–1000 nm), are membrane-bound vesicles actively secreted by various cell types within the hematologic TME. These vesicles, often termed oncosomes when derived from tumor cells, serve as vehicles of intercellular communication that modulate the phenotype and function of recipient cells, promoting tumor progression, immune evasion, and therapy resistance. EVs carry a complex cargo that includes proteins, nucleic acids (mRNA, miRNA, lncRNA), lipids, and metabolites. The composition of this cargo determines their functional impact on the microenvironment. Tumor-derived EVs enriched in pro-oncogenic proteins such as tissue inhibitor of metalloproteinases-1 (TIMP-1) and lipids such as sphingomyelin can enhance malignant cell survival, proliferation, and invasion following uptake by surrounding stromal or immune cells.⁷⁹

In AML, drug-resistant leukemic cells release EVs that contain specific miRNAs and proteins capable of conferring chemoresistance to otherwise sensitive subclones. This horizontal transfer of resistance supports clonal selection and disease persistence under therapeutic pressure. EV-mediated communication also facilitates immune suppression by impairing DC maturation and T-cell activation.⁷⁶

In MM, MSCs secrete EVs that promote myeloma cell proliferation, migration, and survival.⁸⁰ These EVs carry functional molecules such as VEGF and adhesion molecules, which activate survival pathways including PI3K/Akt and MAPK in MM cells. Furthermore, MM-derived EVs contribute to bone disease by inducing osteoclast activation and inhibiting osteoblast differentiation.⁸¹

EVs can also enter systemic circulation and condition distant tissues by forming pre-metastatic niches, a phenomenon observed in both solid and hematologic malignancies. By modulating the extracellular matrix (ECM), immune cell recruitment, and vascular permeability at secondary sites, EVs prepare a favorable environment for future leukemic or myeloma cell infiltration.⁸²

4.4. ECM components

The ECM is a dynamic and multifaceted network of structural and regulatory proteins that provide mechanical support and biochemical signaling within the TME.⁸³ In hematologic malignancies, ECM components not only maintain bone marrow architecture but also modulate key processes such as tumor proliferation, immune evasion, and therapeutic resistance.⁸⁴

Collagen is a major ECM component in the normal bone marrow microenvironment, with collagen type III being predominant. It is primarily synthesized by endothelial cells and fibroblasts. In malignancy, ECM composition and organization are actively remodeled to create a tumor-supportive niche. This remodeling is driven by various matrix-modifying enzymes, including lysyl oxidase (LOX), which catalyzes collagen cross-linking.⁸⁵ Upregulation of LOX and related enzymes leads to bone marrow fibrosis, characterized by excessive deposition of collagen type I and reticulin fibers. Bone marrow fibrosis is frequently observed in MM, AML, and myelofibrosis, and is associated with poor prognosis due to its role in immune suppression and chemotherapy resistance.⁸⁶

ECM proteins also serve as disease-specific biomarkers. Distinct ECM signatures have been identified across hematologic malignancies, with potential diagnostic and prognostic implications. In MM, elevated osteopontin expression correlates with advanced disease and inferior clinical outcomes. In contrast, increased thrombospondin-1 levels have been associated with reduced angiogenesis and improved prognosis. These effects are mediated through ECM–cell interactions involving integrins and other surface receptors that activate intracellular signaling cascades promoting proliferation, migration, adhesion, and survival.⁹

5. TARGETING THE TME: THERAPEUTIC STRATEGIES

TME has emerged as a critical therapeutic target due to its central role in disease progression. Recent strategies aim to disrupt this malignant ecosystem by targeting key components such as stromal cells, immune suppressor populations, EVs, cytokine networks, and metabolic pathways. Monotherapy targeting a single pathway often yields limited efficacy due to compensatory mechanisms within the TME. Therefore, current approaches increasingly emphasize multi-targeted interventions that simultaneously disrupt tumor-intrinsic pathways and the surrounding supportive microenvironment. Some of the TME-targeted therapeutic strategies in hematologic malignancies are listed in Table 2.

Table 2.

Selected TME-targeted therapeutic strategies in hematologic malignancies.

Target/pathway	Therapeutic agent(s)	Mechanism of action	Hematologic malignancies	Clinical status/trial notes
PD-1/PD-L1	Nivolumab, pembrolizumab	Immune checkpoint blockade; restores exhausted T-cell function	Hodgkin lymphoma, DLBCL, MM	FDA-approved in HL; ongoing trials in MM, lymphoma (NCT01592370, NCT03297606 recruiting, NCT04205409 active not recruiting, NCT01953692 completed)
CTLA-4	Ipilimumab	Immune checkpoint blockade; enhances T-cell activation by inhibiting CTLA-4-mediated suppression	NHL, MM (early-stage)	Early-phase (I–II) trials; limited efficacy as monotherapy in hematologic malignancies (NCT03017820 recruiting, NCT01822509 completed
CD19 (CAR-T)	Axicabtagene ciloleucel (Yescarta), Tisagenlecleucel (Kymriah)	Redirects engineered T-cells to kill CD19+ B cells	B-ALL, DLBCL, FL	FDA-approved
BCMA (CAR-T)	Ciltacabtagene autoleucel (Carvykti), Idecabtagene vicleucel (Abecma)	Targets BCMA on plasma cells; induces cytolysis	Relapsed/refractory MM	FDA-approved
CXCR4–CXCL12 Axis	Plerixafor (Mozobil)	Blocks CXCR4–CXCL12 interaction; mobilizes malignant cells from bone marrow niche	AML, CLL, MM	FDA-approved
IL-6 Signaling	Siltuximab, tocilizumab	Neutralizes IL-6 (Siltuximab) or blocks IL-6 receptor (Tocilizumab) to inhibit pro-survival signaling	MM, NHL, CLL	NCT00412321 completed
CD19 × CD3 (BiTE)	Blinatumomab	Bispecific T-cell engager; redirects endogenous T-cells to kill CD19+ B cells	B-ALL, NHL	FDA-approved in B-ALL; NHL (NCT00274742)
LAG-3	Relatlimab, Favezelimab, Fianlimab	Blocks LAG-3 receptor on exhausted T cells; restores T-cell activity	CLL, AML, FL, DLBCL	Phase I/II trials in hematologic malignancies; early data show responses in DLBCL
TIM-3	MBG453 (Novartis), TSR-022 (Tesaro/GSK), Sym023 (Symphogen)	Blocks TIM-3 on T cells and myeloid cells; reverses exhaustion/immunosuppression	AML, B-ALL	Early phase trials: TIM-3/Gal-9 high expression associated with chemotherapy resistance in AML
TIGIT	Tiragolumab, Ociperlimab, Etigilimab	Blocks TIGIT on T/NK cells; enhances T/NK effector function	Lymphoma, myeloma	Preclinical and early clinical data, especially focusing on metabolic/immune interaction and NK-cell effects
VISTA	Clinical candidates (CI-8993); no mature drug yet	Inhibit T-cell activation through VISTA pathway; highly expressed in hematologic TME	AML, MM	Drug development in preclinical stage
B7-H3/B7-H4	Enoblituzumab	Immune checkpoint of B7 family; modulates T-cell and myeloid cell responses	ENKTCL	Mechanistic studies show B7-H3 in TME; Clinical trials are less mature in hematologic cancers

AML = acute myeloid leukemia, B-ALL = B cell acute lymphoblastic leukemia, BCMA = B-cell maturation antigen, CAR = chimeric antigen receptor, CLL = chronic lymphocytic leukemia, CTLA-4 = cytotoxic T-lymphocyte-associated antigen-4, CXCL12 = C-X-C motif chemokine ligand, DLBCL = diffuse large B-cell lymphoma, ENKTCL = extranodal NK/T-cell lymphoma, FDA = Food and Drug Administration, FL = follicular lymphoma, HL = Hodgkin lymphoma, IL = interleukin, LAG-3 = lymphocyte-activation gene 3, MM = multiple myeloma, NHL = non-Hodgkin’s lymphoma, NK = natural killer, PD-1 = programmed death-1, PD-L1 = programmed death-ligand 1, TIGIT = T-cell immunoreceptor with immunoglobulin and ITIM domains, TIM = The T-cell immunoglobulin and mucin structural domain (TIM) family, TME = tumor microenvironment, VISTA = V-domain immunoglobulin suppressor of T-cell activation.

Therapeutic efforts under investigation focus not only on eliminating malignant hematopoietic cells but also on reprogramming or neutralizing the supportive signals from neighboring cells, including MSCs, CAFs, TAMs, and endothelial cells. Additionally, targeting soluble factors such as cytokines, chemokines, and growth factors, as well as ECM remodeling enzymes, has shown potential to impair TME-mediated resistance. Ultimately, the TME plays a decisive role in shaping the clinical course of hematologic malignancies. Effective therapeutic strategies must integrate both tumor-directed and microenvironment-targeted modalities to improve patient outcomes and overcome treatment resistance. Key strategies to target the TME in hematological malignancies include immune checkpoint inhibitors (ICIs), CAR-T cell therapy, disruption of cytokine and chemokine signaling, and modulation of stromal and myeloid cell populations.^7,66,87,88

5.1. Immune checkpoint inhibitors

Immune checkpoints are regulatory pathways that maintain immune homeostasis by preventing excessive T-cell activation and preserving self-tolerance. Key checkpoint molecules include programmed death-1 (PD-1), PD-L1, and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). In hematologic malignancies, tumor cells exploit these pathways to suppress anti-tumor immunity, leading to T-cell exhaustion and diminished cytotoxic responses.^57,89,90

ICIs targeting PD-1, PD-L1, and CTLA-4 have emerged as promising immunotherapeutic agents capable of restoring T-cell function and enhancing tumor clearance. Among hematologic cancers, classical Hodgkin lymphoma (cHL) has demonstrated the most robust response to checkpoint blockade. In cHL, tumor cells frequently exhibit 9p24.1 amplification, resulting in overexpression of PD-L1 and PD-L2. Treatment with nivolumab, an anti-PD-1 monoclonal antibody, reactivates exhausted T cells and has shown high overall response rates and durable remissions in relapsed or refractory cHL.⁹¹

In contrast, the efficacy of ICIs in other hematologic malignancies, such as MM and AML, has been limited. These malignancies often feature a profoundly immunosuppressive bone marrow TME, characterized by low infiltration of functional effector T cells and high levels of regulatory or suppressive immune populations.⁸⁹ Additionally, low baseline expression of PD-L1 on tumor cells contributes to reduced therapeutic responsiveness. Combinatorial strategies are under investigation to enhance the efficacy of ICIs in these settings. These include co-administration with hypomethylating agents (which upregulate antigen presentation and PD-L1 expression), monoclonal antibodies targeting tumor-specific antigens, and chimeric antigen receptor (CAR)-T cell therapy, which can be synergistically potentiated by checkpoint blockade.⁸⁸ Beyond these classical immune checkpoints, several emerging inhibitory receptors have gained attention as novel immunotherapeutic targets in hematologic malignancies. These include LAG-3, TIM-3, T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), V-domain immunoglobulin suppressor of T-cell activation (VISTA), and B7-H3/B7-H4 (Table 2).^92,93

5.2. CAR-T cell therapy: interactions with the TME

CAR-T cell therapy has revolutionized the treatment of hematologic malignancies by enabling precise, antigen-specific immune targeting. This modality involves the ex vivo genetic engineering of autologous T cells to express CARs, which are synthetic constructs composed of an extracellular single-chain variable fragment (scFv) for antigen recognition, a transmembrane domain, and intracellular signaling domains such as CD3ζ and costimulatory motifs (CD28 or 4-1BB).⁹⁴ These engineered receptors enable T cells to recognize and eliminate malignant cells expressing specific surface antigens independently of MHC presentation, thereby circumventing a common mechanism of tumor immune escape. Upon infusion, CAR-T cells expand, persist, and mediate potent cytotoxicity against tumor cells, resulting in durable clinical responses in various leukemias, lymphomas, and MM.⁹⁴

One of the most successful applications of CAR-T cell therapy has been the targeting of CD19, a pan–B-cell surface antigen, in B-cell malignancies such as acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma. Tisagenlecleucel (Kymriah), the first Food and Drug Administration (FDA)-approved CAR-T product, demonstrated complete remission rates of up to 81% in pediatric and young adult patients with relapsed or refractory B-ALL.⁹⁵ Similarly, axicabtagene ciloleucel (Yescarta) has shown high and durable response rates in relapsed or refractory DLBCL and other non-Hodgkin lymphomas, including follicular and marginal zone lymphoma. In pivotal trials, axi-cel achieved complete remission in nearly 80% of patients with follicular lymphoma, with a substantial proportion maintaining durable responses beyond 3 years. Long-term follow-up data indicate overall response rates of 94% in follicular lymphoma and 77% in marginal zone lymphoma, with durable remissions observed in a subset of patients and manageable safety profiles, although efficacy may be reduced in those with prior bendamustine exposure or high metabolic tumor burden.⁹⁶ Figure 2A shows the therapeutic strategies in hematological malignancies, while Figure 2B shows some of the FDA-approved CAR-T cell therapies for different hematological malignancies.

Figure 2.

Current therapeutic appraoches targeting lymphocytic malegnencies. (A) Therapeutic strategies targeting malignant B lymphocytes in the treatment of hematological malignancies. Immune checkpoint inhibition: anti-PD-1 antibodies block the PD-1 pathway to enhance immune-mediated tumor cell killing. CAR-T cell therapy: anti-CD19 CAR-T cells target and eliminate CD19-expressing malignant B cells. IL-6 signaling blockade: siltuximab inhibits IL-6, disrupting pro-tumor signaling and immune evasion. CXCR4–CXCL12 axis inhibition: plerixafor blocks the CXCR4 receptor, interfering with tumor cell migration and microenvironmental support. (B) Approved FDA CAR-T cell therapies: ABECMA uses anti-BCMA to target multiple myeloma B cells. BREYANZI and KYMRIAH use anti-CD19 to target CD19 found on malignant B cells in follicular lymphoma and ALL, respectively. ALL = acute lymphoblastic leukemia, Anti-BCMA = anti-B cell maturation antigen, CAR = chimeric antigen receptor, IL = interleukin, PD-1 = programmed death-1.

In MM, the emergence of B-cell maturation antigen (BCMA) as a therapeutic target has advanced CAR-T cell development.⁹⁷ Idecabtagene vicleucel (ide-cel) achieved a 73% overall response rate and a 33% complete response or better rate in heavily pretreated patients with relapsed/refractory MM, with 26% attaining minimal residual disease-negative status, but caused grade 3/4 toxic effects (primarily hematologic and cytokine release syndrome) in nearly all patients.⁹⁸

Unlike B-cell malignancies, where lineage-restricted antigens (CD19, BCMA) allow CAR-T success, myeloid neoplasms such as AML lack safe, lineage-restricted targets and are more challenging due to the immunosuppressive marrow TME. Antigen heterogeneity (variable CD123/FLT3 expression), antigen loss, T-cell exhaustion, and suppressive myeloid populations limit efficacy and raise safety concerns for on-target myeloablation.⁹⁹ To address these barriers, strategies under study include armored CARs that secrete cytokines, switchable CAR constructs, and combination approaches pairing CAR-T with TME-modulators (CSF1R or CD47 inhibitors) to reduce myeloid suppression and boost persistence.^97,100 Additionally, ongoing research explores CAR-T therapies targeting additional antigens, such as CD22 for CD19-negative relapse in B-ALL.⁴⁵ Strategies such as universal CAR-T cells (allogeneic platforms) are also under investigation to improve safety, efficacy, and scalability.¹⁰⁰

Beyond enhancing CAR-T cell function itself, the field is also exploring entirely novel cellular platforms to overcome the inherent limitations of T-cell therapies. CAR-NK cells provide potent cytotoxic activity with lower risks of graft-versus-host disease and cytokine release syndrome.¹⁰¹ NK cells can be derived from peripheral blood, cord blood, or NK-92 cell lines. Like CAR-T cells, they are then engineered to recognize specific antigens. Early clinical studies have demonstrated their safety and efficacy in patients with relapsed or refractory leukemia and lymphoma.¹⁰² Similarly, CAR-macrophages (CAR-M) represent a novel strategy that reprograms macrophages toward a pro-inflammatory, phagocytic phenotype. Such a phenotype is capable of both antigen presentation and tumor clearance. Preclinical data indicate that CAR-M cells can reprogram the suppressive TME and enhance endogenous T-cell response.¹⁰³ Together, these next-generation cellular approaches highlight the diversification of adoptive immunotherapy beyond conventional CAR-T approaches.

5.3. Cytokine/chemokine signaling disruption

In MM, IL-6 is a key survival factor secreted predominantly by BMSCs. Therapeutic inhibition of IL-6 signaling using monoclonal antibodies such as siltuximab has demonstrated biological activity in early-phase clinical trials.¹⁰⁴ However, its efficacy as monotherapy remains limited, likely due to the multifactorial nature of MM pathogenesis and compensatory survival pathways.¹⁰⁵ Plerixafor, a selective CXCR4 antagonist, disrupts the interaction of leukemic cells with the TME, mobilizing leukemic cells into the peripheral circulation and sensitizing them to chemotherapy.¹⁰

Clinical studies have demonstrated enhanced efficacy when CXCR4 antagonists are combined with cytotoxic or hypomethylating agents, as targeting these chemokine and cytokine pathways not only disrupts malignant-stroma interactions but also modulates the immune microenvironment. IL-6 blockade may relieve T-cell suppression and reduce MDSC expansion, while CXCR4 inhibition enhances immune infiltration and antigen presentation.¹⁰⁶

5.4. Targeting TAMs and other stromal cells

Therapeutic interference with the signaling networks represents a promising strategy to reprogram the TME toward a more immunogenic and treatment-responsive state. To counteract these pro-tumoral roles, several therapeutic strategies targeting TAMs are under active investigation. Therapeutic strategies include depleting TAMs, reprogramming them from M2 to M1, and blocking their recruitment or immunosuppressive functions. Colony-stimulating factor 1 receptor (CSF1R) inhibitors have reduced TAM numbers and reprogrammed macrophage phenotype in early clinical studies, with correlative data linking TAM depletion to improved chemosensitivity. Moreover, anti-CD47 therapies (targeting the CD47/SIRPα phagocytosis checkpoint) have shown early clinical promise in AML and NHL. These “don’t eat me” signals protect malignant cells from macrophage-mediated phagocytosis. Therefore, anti-CD47 is actively being combined with cytotoxic or targeted agents to convert immune suppression into effective phagocytic clearance.⁴⁵ Additionally, targeting stromal cells such as mesenchymal stromal cells is under investigation, as these cells support malignant cell survival, promote immunosuppression, and contribute to chemoresistance in the bone marrow niche.¹²

5.5. Modulating metabolic pathways in the TME

Metabolic reprogramming is a hallmark of malignancies, affecting both malignant and stromal cells in the TME.¹⁰⁷ Targeting these dysregulated metabolic pathways has emerged as a promising strategy to disrupt tumor survival and counteract immunosuppression-specific approaches under investigation include glutaminase inhibitors and Arg/IDO1 pathway inhibitors, aimed at reversing amino-acid depletion and T-cell suppression, as well as FAO inhibitors, designed to disrupt fatty-acid-dependent survival in MM and AML.^108,109 Combining metabolic inhibitors with proteasome inhibitors in MM, or with hypomethylating agents, or FLT3 inhibitors in AML, provides a mechanistic approach to deplete metabolic reserves while restoring effector T-cell function.¹⁰⁹ Similarly, in leukemia, targeting metabolic vulnerabilities, such as IDO1-mediated tryptophan catabolism or FAO, can restore anti-tumor immunity and sensitize malignant cells to therapy.¹⁰⁸

5.6. Anti-angiogenic and vascular-targeted therapies

Angiogenesis within the bone marrow and lymphoid microenvironments plays a crucial role in the progression and therapeutic resistance of hematological malignancies.³⁸ Targeting this abnormal vasculature has shown promising preclinical and early clinical results. Agents that inhibit VEGF/VEGFR pathways or modulate angiogenic signaling, such as bevacizumab and multitargeted TKIs, can normalize vascular architecture, reduce hypoxia, and enhance drug penetration.¹¹⁰ In MM and myeloproliferative neoplasms, clinical trials have explored anti-angiogenic strategies in combination with immunomodulatory or cytotoxic agents, improving response durability.¹¹¹

5.7. Combination therapies

The complexity of the hematologic TME has driven a shift toward combination strategies that integrate immune, stromal, and metabolic targeting. These multi-modal approaches aim to overcome the protective mechanisms that often limit monotherapy efficacy. Immunotherapies, such as checkpoint inhibitors and CAR-T cells, exhibit enhanced activity when combined with agents that reprogram the TME toward a more permissive immune landscape.¹⁴ the PD-1 inhibitor nivolumab may achieve greater efficacy in myeloid malignancies when administered alongside stromal modulators that reduce immune suppression.^12,89

Similarly, idecabtagne vicleucel could benefit from co-administration with cytokine pathway inhibitors, such as siltuximab (anti-IL-6 antibody) or plerixafor (CXCR4 antagonist). This would disrupt stromal-derived pro-survival signaling and improve immune infiltration.^98,105 Targeting TAMs by blocking CSF1R or inhibiting the CD47/SIRPα axis may also synergize with checkpoint blockade, enhancing phagocytic clearance and reducing IL-10-mediated suppression.^12,70 Moreover, combining immunotherapy with metabolic modulators, like glutaminase inhibitors, can reduce nutrient competition. Additionally, it could reverse T-cell exhaustion, thereby improving anti-tumor cytotoxicity.^74,107,109 Most evidence for these synergistic effects derives from preclinical knockout or pharmacologic models.^112,113 Ongoing clinical studies will determine whether these findings translate to patient outcomes.

6. CHALLENGES AND FUTURE DIRECTIONS

Despite substantial advances in characterizing the TME in hematologic malignancies, several critical challenges persist. The TME is inherently complex, highly dynamic, and heterogeneous, which complicates the development of universally effective therapeutic strategies. Variability in TME composition across different disease subtypes, individual patients, and disease stages limits the applicability of one-size-fits-all approaches.

Although preclinical models have been instrumental in elucidating TME mechanisms, they fail to fully replicate the cellular and molecular architecture of the human bone marrow niche. This discrepancy restricts their translational relevance and reduces predictive accuracy for clinical outcomes. While innovative therapies, such as ICIs, CAR-T cell therapy, and cytokine/chemokine modulators, have demonstrated clinical promise, significant barriers remain. Resistance to treatment, immune-related toxicity, and disease relapse are frequent and often difficult to manage.⁹⁹

It has been observed that the efficacy of checkpoint blockade has limited success in myeloid malignancies, where profound immune suppression prevails.^96,114 Moreover, targeting stromal or immune components of the TME without disrupting normal hematopoiesis remains a major therapeutic challenge. This underscores the need for combination strategies that concurrently target malignant clones and reprogram the supportive niche. The integration of immunometabolism, spatial transcriptomics, and multi-omics profiling will likely redefine therapeutic decision-making in the near future. Spatial transcriptomics can map Treg/TAM niches and identify patients likely to respond to macrophage-directed therapies.¹⁰⁷ Targeting the hematologic TME should no longer be considered an adjunct to direct tumor cytotoxicity; it must be positioned as a core pillar of modern therapy.

7. CONCLUSION

The TME is more than just an environment surrounding cancer cells; it is an active and dynamic participant in disease progression. It can affect therapy resistance, immune evasion, organ infiltration, and several other processes that favor the malignant cells. Interactions among stromal cells, immune suppressor cells, and molecular mediators such as cytokines and chemokines support tumor survival and limit treatment efficacy. Research has progressed significantly over the years, uncovering this complex web of interactions in hematologic malignancies and exploring new therapeutic approaches. However, challenges like therapeutic resistance and selective targeting persist. Although many TME interactions are mechanistically defined through knockout or pharmacologic studies, others remain correlative and warrant direct functional validation to strengthen translational relevance. Therefore, there is still much to explore as future success will depend on the ability to convert this accumulating knowledge into personalized and TME-targeted therapies through integrating immune profiling and precision technologies. This will enable the elimination of the cancer cells and the reprogramming of the TME, support remission, and improve clinical outcomes.