Review ArticleReview
Open Access

Adenosine signaling in tumor-associated macrophages and targeting adenosine signaling for cancer therapy

Lei Yang, Yi Zhang and Li Yang
Cancer Biology & Medicine November 2024, 21 (11) 995-1011; DOI: https://doi.org/10.20892/j.issn.2095-3941.2024.0228

Abstract

This review examined the critical role of adenosine signaling in modulating the behavior of tumor-associated macrophages (TAMs), a key determinant of the tumor microenvironment (TME). Adenosine is an immunosuppressive metabolite that is highly enriched in the TME due to elevated expression of adenosine triphosphatase (ATPase). Adenosine influences polarization of TAMs through A2A and A2B receptors, which drives a phenotype that supports tumor progression and immune evasion. The adenosine-mediated regulation of TAMs significantly suppresses the TME, dampening the efficacy of current immunotherapies. Targeting the adenosine pathway has shown potential in preclinical studies through reversal of the immunosuppressive microenvironment and antitumor immune response enhancement. Clinical trials are currently underway to determine the impact of A2A receptor antagonists, and CD39 and CD73 inhibition, enzymes that are pivotal in adenosine production, in various cancers. The current understanding of the CD39-CD73-adenosine axis in TAM regulation and the emerging strategies targeting adenosine signaling pathway for therapeutic intervention are the subjects of this review. The current clinical trials focusing on adenosine pathway inhibitors in combination with existing therapies to improve clinical outcomes are summarized and the need for continued research to refine these approaches for cancer treatment is emphasized.

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Introduction

Adenosine is a pivotal regulator of cellular metabolism and a key mediator of immune responses. This purine nucleoside has emerged as a pivotal element in the complex interplay between cancer cells and the immune system. Adenosine, which is present at low concentrations under normal physiologic conditions, accumulates in the tumor microenvironment (TME) owing to hypoxic and catabolic stresses characteristic of solid malignancies1,2. Production of adenosine in the TME is facilitated by the action of ecto-enzymes (CD39 and CD73), which convert extracellular adenosine triphosphate (ATP) to adenosine, thereby contributing to the immunosuppressive environment. The TME, a dynamic and heterogeneous milieu, is shaped by bidirectional crosstalk between cancer cells, immune cells, and the extracellular matrix3. In this context, adenosine and its receptors have been recognized for their profound influence on the polarization and function of macrophages, which are innate immune cells that can promote or suppress tumor progression.

Macrophages are highly plastic and can exhibit a range of activation states between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes4,5. Tumor-associated macrophages (TAMs) are some of the most abundant immune cells within tumors and participate in the formation of the TME6. TAMs are intricately regulated by a spectrum of signaling pathways that dictate their polarization states, which are pivotal in immune responses and tissue repair. Cytokines, like interleukin (IL)-4 and IL-13, activate the JAK-STAT pathway to promote M2 polarization7. The PI3K-Akt pathway is also essential for metabolic regulation in macrophages and influences the M1 and M2 states8. Macrophage polarization in the TME is subject to multiple regulatory mechanisms, including the adenosine signaling pathway. Adenosine receptors (ARs), such as A2A and A2B, are upregulated in macrophages present in the TME and can modulate their functional profiles. This effect often leads to a suppressive phenotype that promotes tumor growth and metastasis.

Therefore, the adenosine signaling pathway represents a critical node in the network of interactions that govern tumor immune dynamics. By engaging ARs, the adenosine signaling pathway dampens anti-tumor immune responses, enhances the immunosuppressive functions of macrophages, and contributes to the establishment of an immunosuppressive TME. Therapies aimed at the adenosine pathway, especially when combined with immune checkpoint inhibitors, have demonstrated potential in preclinical models and are now under investigation in clinical trials.

In this review we sought to deliver a comprehensive analysis of the complex role of adenosine within the TME, with a particular focus on the influence of adenosine on macrophage function and subsequent effects on tumor immunity. By examining the current literature we aimed to offer a detailed exploration of the molecular mechanisms that underlie adenosine-mediated immune modulation and investigate the potential therapeutic applications of targeting this pathway in cancer treatment.

Generation and physiologic roles of adenosine

Adenosine is mainly derived from ATP hydrolysis, while intracellular adenosine may be released from cells during apoptosis9,10. Inflammatory conditions can induce the release of ATP and adenosine diphosphate (ADP), which are hydrolyzed rapidly into adenosine through a series of reactions. CD39/CD73 is the most studied pathway that converts ATP into adenosine. CD39 belongs to the NTPDase family and is responsible for conversion of ATP into AMP. CD73 mediates the conversion of AMP into adenosine. CD39 is constitutively expressed in the spleen, thymus, lungs, and placenta11,12 and CD73 is widely expressed on many tissues, including the colon, brain, kidneys, liver, and heart13. The CD38-ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1)-CD73 axis is another pathway by which extracelluar adenosine is generated. CD38 converts NAD+ into adenosine diphosphate ribose (ADPR) and ENPP1 further degrades ADPR into adenosine monophosphate (AMP)14,15. Adenosine is also generated from dephosphorylation of ATP and ADP by the alkaline phosphatase family (Figure 1). Extracellular adenosine is eliminated by phosphorylation to adenosine monophosphate or by deamination to inosine. Adenosine has the following pleiotropic effects: heart rate disturbances when injected intravenously; induces vasodilation in the cardiovascular system16; serves as a distress signal in pathology and a physiologic regulator; and widely accepted as an endogenous sleep-regulatory substance in which the adenosine level increases upon sleep deprivation17.

Figure 1
Figure 1

Generation of extracellular adenosine. Adenosine can be released into the extracellular space directly. CD39–CD73-mediated hydrolysis of ATP is the main resource of extracellular adenosine. CD38-ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) axis-mediated conversion of nicotinamide adenine dinucleotide (NAD+) into AMP and subsequent AMP degradation by CD73 is another source of adenosine. Alkaline phosphatases (ALPs) are also implicated in adenosine production through hydrolysis of extracellular ATP/ADP/AMP. ATP, adenosine triphosphate; ADP, adenosine diphosphate; AMP, adenosine monophosphate.

There are four ARs (A1, A2A, A2B, and A3). Each of these receptors is classified as a G protein-coupled receptor (GPCR)18. A1R and A3R are coupled to Gi proteins, whereas A2AR and A2BR are coupled to Gs proteins (Figure 2). Therefore, A2AR/A2BR activation increases cyclic AMP production, activates protein kinase A (PKA), and phosphorylates the cyclic AMP response element binding protein (CREB). In contrast, A1R/A3R activation decreases cyclic AMP production and suppresses PKA and CREB. In addition to cyclic adenosine monophosphate (cAMP) signaling, there are other signaling pathways coupled to these adenosine receptors. A3R induces phospholipase C (PLC)-β signaling, thus inducing diacylglycerol (DAG) and 1,4,5-triphosphate (IP3) production and leading to a rise in the cellular Ca2+ concentration. It has also been reported that A1R is coupled to the MAPK signaling pathway. For example, Vyas et al.19 reported that A1R activates p38, extracellular signal-regulated kinase (ERK), and JNK phosphorylation and regulates tissue transglutaminase (TG2) activity in H9c2 cells. A2AR activation stimulates MAPK and protein kinase B (Akt) signaling20. A2BR also triggers PLC activation by enrolling Gq protein21. In addition, A2BR is coupled to MAPK and Akt and is therefore involved in many phosphorylation process22. A3R has been implicated in signal transduction through ERK1/2, p38, and JNK23. A3R activation also modulates PI3K/Akt and NF-κB transduction and therefore exerts anti-inflammatory effects24.

Figure 2
Figure 2

Adenosine receptor signaling pathway. A1R and A3R are coupled to Gi proteins, whereas A2AR and A2BR are coupled to Gs proteins. Grey line: activation of A2AR and A2BR leads to increased cyclic adenosine monophosphate (cAMP) production, while A1R and A3R trigger a decrease in cAMP production, which is involved in PKA-mediated phosphorylation of CREB. Blue line: in addition to the effects on the cAMP pathway, all four types of adenosine receptors also interact with PI3K/Akt and MAPK cascades. Red line: A2BR and A3R also activate PLC through Gq and are implicated in DAG/PKC and Ca2+ signaling. PLC, phospholipase C; IP3, inositol trisphosphate; DAG, diacylglycerol; PKC, protein kinase C; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; PKC, protein kinase C; MAPK, mitogen-activated protein kinase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CREB, cAMP-response element binding protein.

Adenosine signaling pathway in the TME

Adenosine accumulation in the TME favors tumor growth and metastasis through direct activation of A2BR on tumor cells25. CD73 expression is directly associated with ovarian cancer cell proliferation26 and CD73 expression on cancer-associated fibroblasts (CAFs) also promotes tumor growth in mice. A1R is overexpressed in human colorectal27 and lung cancer28. Both pro- and anti-tumor roles of A1R have been reported18. A recent study showed that A2AR is mainly expressed on natural killer (NK) and T cells but not expressed on B cells. A2AR expression on tumor infiltrating lymphocytes is increased compared to counterparts in tumor-draining lymph nodes29. A2AR expression is significantly higher on CD11b+ cDC2 cells relative to all other myeloid cell subsets. A2BR is expressed in immune and non-immune cells. Cekic et al.30 reported that an A2BR antagonist slows the growth of MB49 bladder and 4T1 breast tumors in syngeneic mice and reduces metastasis of breast cancer cells. Yang et al.31 reported that A2BR is highly expressed on smooth muscle cells, endothelial cells, and macrophages and emphasized a role for A2BAR in attenuating inflammation. A3R is overexpressed in a large number of cancer types32.

Adenosine signaling pathway in TAMs

It is now recognized that adenosine receptor expression undergoes dynamic changes during development and activation on the surface of macrophages and dendritic cells (DCs)33. AR expression is upregulated on M1 macrophages. For example, Buenestado et al.34 reported that A2AR expression on macrophages increases significantly following lipopolysaccharide (LPS) stimulation. A2BR expression is upregulated by IFN-γ on murine bone marrow-derived macrophages (BMDMs)35, which could be a feedback mechanism for macrophages deactivation. Together, these studies indicated a higher level of A2AR/A2BR expression on M1 macrophages, which is consistent with the well-documented immune regulatory function. The level of CD39 and CD73 expression is decreased on M1 macrophages and increased on M2 macrophages36. TAMs are a heterogeneous plastic subset of tumor-infiltrating immune cells. TAMs are involved in tumor initiation, progression, angiogenesis, and metastasis37,38. Over the past few decades, numerous strategies have been proposed to target TAMs for anti-tumor purposes39–42, with one crucial aspect being the reprogramming of TAMs from a pro-tumor to an anti-tumor phenotype43. Adenosine is a key regulator in shaping the function of TAMs33,44,45. Montalbán et al.46 reported that CD39 and CD73 expression in monocytes and peritoneal macrophages is negligible from healthy donor and M1 macrophages, while CD39 and CD73 expression is upregulated on TAMs46. CD39 and CD73 are highly expressed on human46 and murine47,48 macrophages after co-culture with cancer cells in vitro. This is in agreement with the immunosuppressive regulatory function of adenosine on macrophages.

Targeting adenosine signaling in TAMs may serve as a promising strategy to enhance anti-tumor therapy. The expression of ARs on macrophages is constantly altered during differentiation and polarization. Adenosine signaling through various receptors induces different macrophage cascades, leading to a plethora of distinct events. Macrophages polarize into different states in the spectra of classical and alternative activation. Macrophages activate distinct functional programs in response to various stimuli. When macrophages encounter danger signals, such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), or T helper (Th) type 1 cytokines, macrophages polarize into an M1 phenotype to protect the host from pathogen invasion49,50. M1 macrophages are characterized by high levels of reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-α), ILs, such as IL-1β, IL-6, IL-12, IL-18, and IL-23, and other chemokines, such as C-X-C motif chemokine ligand 5 (CXCL5). When activated by Th2 cytokines, such as IL-4 and IL-13, macrophages undergo alternative (M2) polarization and produce anti-inflammatory cytokines, such as IL-10 and transforming growth factor-beta (TGF-β)51. TAMs are modulated by adenosine to differentiate into an immunosuppressive phenotype and function as a source of adenosine46,52. Adenosine is involved in numerous aspects of TAM function and has an important role in TME regulation. Targeting TAMs has efficacy in boosting immunotherapy and adenosine signaling has garnered significant interest.

Adenosine signaling pathway in T cells

T cells are an important subpopulation in the TME and the anti-tumor function of T cells is widely documented to be dampened by adenosine in the TME. Th1, Th2, and Th17 cell activation is suppressed in the presence of adenosine and cytokine production is inhibited53. A2AR is the main AR expressed on T cells and A2AR activation counteracts T cell receptor (TCR)-mediated T cell activation by increasing intracellular cAMP54. A2AR-mediated increase in cAMP is associated with reduced IFN-γ and granzyme B production in CD8+ T cells. The effect of A2AR agonists can be abrogated using A2AR antagonists55. A2AR-mediated T cell function suppression is critical for cancer cell evasion of immune surveillance. It has recently been reported that A2AR signaling modulates CD8+ T cell function through fine-tuning metabolic fitness of T cells56. Adenosine-rich TME may suppress T cell anti-tumor function and block A2AR using A2AR antagonists has shown promising results in cancer treatment57.

Adenosine signaling pathway in NK cells

Tumor-produced adenosine inhibits NK cell activity and cytokine production and thereby protects tumor cells from immune system killing58. A2AR acts as a checkpoint that limits NK cell maturation59 and targeting A2AR on NK cells delays tumor growth. CD39, the pivotal enzyme for adenosine production in TME, is upregulated on tumor-infiltrated NK cell compared with circulating counterparts. Inhibiting NTPDase activity has been reported to suppress metastases in different tumor models and the effect is dependent on NK cells and IFN-γ60,61. Higher expression of A3R has been detected in tumor-infiltrating NK cells compared to peripheral NK cells and the level of A3R expression is negatively correlated with tumor-infiltrating NK cells62.

Adenosine signaling pathway in DCs

A1R, A2AR, and A3R are expressed on human DCs. AR activation has been reported to influence DC differentiation. A2AR and A2BR signaling promote IL-10, vascular endothelial growth factor (VEGF), and TGF-β expression, while suppressing the expression of pro-inflammatory IL-12, CD80, and CD8663. Challier et al.64 reported that adenosine skews DCs into a more tolerogenic phenotype, which is less able to prime CD8+ T cells. The adenosine analog, 5′-(N-ethylcarboxamido) adenosine (NECA), inhibits IL-12 and IL-23 production of DCs, thus promoting a Th2 response and immune tolerance65. Bergamin et al.66 reported that adenosine increases IL-10 secretion, while inhibiting IL-12 and TNF-α of DCs.

Effect of adenosine signaling pathway on TAMs

The adenosine signaling pathway is a multifaceted regulator of TAMs with significant implications for cancer progression and immunity. The adenosine signaling pathway is involved in regulating TAM phenotype and function (mainly TAM accumulation, proliferation, polarization, cytokine production, and angiogenesis function67–69). Understanding the adenosine signaling pathway in TAMs favors the development of strategies to target TAMs for cancer therapy (Figure 3).

Figure 3
Figure 3

Overview of adenosine signaling in TAMs. Adenosine affects TAM accumulation, polarization, cytokine production, and angiogenesis within the TME. (A) Increasing TAM accumulation in the TME. Adenosine-rich TME promotes monocyte migration into tumor sites, thus increasing TAM accumulation. (B) Influencing macrophage polarization. Adenosine is involved in promoting macrophage polarization towards an M2-like phenotype through A1/2A/2B receptors, leading to the upregulation of ARG-1 and downregulation of iNOS expression. (C) Influencing macrophage cytokine production. Adenosine is implicated in regulating cytokine expression of macrophage. Activation of A2AR results in an increase in IL-10 and TGF-β, and a decrease in TNF-α, IL-8, IL-6, IL-12, and MIP-1α. (D) Regulating angiogenesis function. Adenosine signaling modulates the angiogenic function of TAMs by inducing VEGF production, potentially through A2AR and A2BR pathways. TAM, tumor-associated macrophage; TME, tumor microenvironment; ADO, adenosine; TNF-α, tumor necrosis factor-α; MIP1-α, macrophage inflammatory protein-1-α; iNOS, inducible nitric oxide synthase; VEGF, vascular endothelial growth factor; ARG-1, arginase 1.

Increasing TAM accumulation

Numerous studies have revealed that the abundant presence of TAMs in tumors is associated with a poor prognosis70–73. Circulating monocytes have a crucial role in the accumulation of TAMs in the TME74,75. These monocytes exit blood vessels and migrate into tissues. Once stimulated by local growth factors and cytokines, these cells differentiate into macrophages or DCs76. Selective activation of ARs (A1, A2, and A3) has been shown to increase macrophage infiltration in a B16 tumor mouse model77. Among the ARs, A3R has the most significant effect on upregulation of macrophage infiltration, whereas A1R and A2R exhibit comparatively minor effects. In addition to a role in monocyte recruitment, ARs may promote self-renewal of tumor-resident TAMs. A recent study showed that tumor-derived adenosine stimulates macrophage proliferation in human hepatocellular carcinoma by increasing macrophage proliferation locally in the TME78. It was shown that adenosine exerts its effects on human macrophage proliferation through the A2A receptor, and the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase kinase (MEK)/ERK signaling pathways. In contrast, Xaus et al.79 reported that adenosine inhibits macrophage proliferation via A2BR signaling in a colony-stimulating factor-dependent manner. These contrasting effects on macrophage proliferation may be attributed to the activation of different AR subtypes and their downstream responses. In another study researchers observed that blocking the CD39/CD73 pathway markedly reduced monocyte migration into ovarian cancer tissues46. A recent single cell analysis revealed that pro-tumor SPP1+ macrophages80 are enriched in a high-adenosine microenvironment. The adenosine antagonist, ZM241385, decreased the accumulation of CD206+ macrophages and SPP1 secretion in lung cancer mouse model81. Targeting adenosine signaling to prevent the recruitment of monocytes into tumors represent a strategic approach for curbing tumor accumulation.

Regulating macrophage polarization

Over the past few decades, a multitude of studies have documented macrophage polarization. Macrophages, a plastic cell population, exhibit distinct gene expression patterns when exposed to different stimuli82. M1-polarized macrophages, also known as canonically activated macrophages, are triggered by LPS, IFN-γ, and granulocyte macrophage colony stimulation factor (GM-CSF). Macrophages undergo alternative activation, known as M2 polarization, upon stimulation with IL-4, IL-10, or IL-13. M2 macrophages can be further categorized into the following subtypes based on the stimuli: M2a; M2b; M2c; and M2d83–85. However, the M1/M2 dichotomy is considered an oversimplification and may not adequately capture the full complexity of TAM polarization. TAMs within tumors represent a complex and heterogeneous population that is characterized by diverse phenotypes, origins, and genetic programs86,87.

Adenosine promotes alternative macrophage polarization88–90. The anti-inflammatory effects observed in macrophages are mediated by the activation of ARs, including A2A, A2B, and A3R. Studies have reported that M2-polarized macrophages have elevated levels of CD39 and CD73 expression, which bolsters the capacity to generate adenosine91. A feedback mechanism in IFN-γ-activated macrophages upregulates A2BR expression and inhibits IFN-γ-induced MHC-II gene upregulation, nitric oxide synthesis, and several pro-inflammatory cytokines35. IL-10-induced alternatively activated M2c macrophages are augmented by A2BR activation92. Activation of A2BR enhances the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which is induced by IL-10, as well as increased expression of TIMP-1 and aginase-1. In another study, researchers found that Toll-like receptor (TLR) stimulation results in the expression of A2BR, leading to an immunoregulatory phenotype in macrophages, and upregulation of A2BR was prevented by IFN-γ treatment93. IFN-γ-mediated A2BR blockade prolongs inflammatory cytokine production by macrophages in response to TLR ligation. Deletion of A2AR in myeloid cells improves anti-tumor immunity47. A2AR-deficient myeloid cells suppress tumor growth, which is dependent on CD8+ T and NK cells. TAMs lacking A2AR exhibit characteristics similar to M1-polarized macrophages, including increased expression of MHC-II and IL-12, along with decreased expression of IL-10. Costales et al.94 showed that Salmonella whole-cell lysate treatment downregulated CD73 expression in RAW264.7 and increased expression of pro-inflammatory cytokines and iNOS. Pharmacologic inhibition of CD73 in RAW264.7 cells enhanced the pro-inflammatory response, while macrophages from CD73-deficient mice demonstrated improved anti-bacterial immune responses. This finding suggested that macrophages in CD73-deficient mice exhibit a more M1-polarized phenotype. TAMs reprogramming is a widely used strategy for reshaping the immunosuppressive TME to augment immunotherapy efficacy. Therefore, targeting adenosine signaling has emerged as a plausible approach to facilitate TAM reprogramming.

Modulating TAM cytokine production

TAMs create an immunosuppressive TME by producing cytokines. Numerous studies have shown that cytokines produced by TAMs facilitate tumor progression. Fan et al.95 found that TGF-β secreted by TAMs promotes tumor cell stemness via transforming growth factor. IL-6 secreted by TAMs also has a key role in promoting tumor growth and invasion96,97. IL-10, an immune-regulatory cytokine produced by M2 macrophages, suppresses CD4+ T cell proliferation and cytokine production98. IL-10 has also been shown to correlate with late-stage lung cancer and may be involved in the progression of non-small cell lung cancer99.

Adenosine concentration in the extracellular space is controlled by the CD39/CD73 system, which is important for fine-tuning the cytokine secretion profile of macrophages. Activation of ARs blocks the release of pro-inflammatory cytokines in macrophages, such as TNF-α, IL-1β, IL-6, IL-12, and nitric oxide100,101. CD39 deficiency in murine macrophages results in higher IL-1β expression via a purinergic receptor (P2X) 7-dependent mechanism102. Stimulation of ARs by agonists affects LPS-induced production of IL-10, TNF-α, and NO in vitro and in vivo. An A1 AR agonist reduces LPS-induced plasma TNF-α levels, while increasing IL-10 levels. Activation of the A3 AR enhances LPS-stimulated IL-10 production and suppresses TNF-α production103. IL-10 expression is augmented by A2BR activation via a post-translational mechanism104. A2BR agonists induce IL-10 production in murine microglia. Using different agonists for different ARs and AR activation was shown to have a major role in stimulating IL-10, leading to accumulation of IL-10 transcription105. Adenosine treatment increases monocyte chemoattractant protein-1 (MCP-1) secretion in tumor supernatant-cultured macrophages, which is reversed by caffeine or A2AR selective antagonist66. Macrophages exposed to tumor-conditioned medium do not exhibit an additional increase in IL-10 release following adenosine treatment. However, the A2AR antagonist reversed this cytokine secretion, suggesting an significant role for adenosine in promoting anti-inflammatory cytokine secretion by macrophages in the TME. Kreckler et al.106 reported that A2AR activation suppresses production of the pro-inflammatory cytokine, TNF-α, induced by LPS in murine macrophages at the gene transcription level. This suppressive effect is cAMP-dependent106. Haskó et al.107 reported that adenosine signaling suppresses IL-12 and TNF-α production by macrophages. Using A2AR-deficient mice, Haskó et al.107 concluded that this suppression was partly dependent on A2AR. Pretreatment of peritoneal macrophages with adenosine significantly increased IL-10 transcription following LPS stimulation107. TAMs contribute to the creation of an immunosuppressive TME by producing a variety of chemokines and cytokines. Adenosine signaling influences the cytokine profile of TAMs, predominantly promoting the production of anti-inflammatory cytokines, which may adversely affect the efficacy of immunotherapy. Blocking adenosine signaling in TAMs presents a promising strategy for reshaping cytokine profiles and enhancing the efficacy of immunotherapy.

Enhancing the angiogenesis function of TAMs

Angiogenesis, the process of generating new blood vessels, can facilitate tumor growth, invasion, and metastasis108. TAMs are crucial drivers of angiogenesis, which supports tumor growth in mouse models (mainly through VEGF secretion109,110). One of the key mechanisms by which TAMs promote tumor progression is by increasing VEGF expression, thereby supporting vessel formation in tumors. Adenosine modulates macrophages angiogenesis function77. A2AR activation induces strong VEGF expression in murine macrophages in hypoxia- and NO-independent manners111. The induction of VEGF by NECA, which is a non-selective adenosine receptor agonist, or by CGS-21680, an A2AR-specific agonist, was largely eliminated in macrophages derived from A2AR knockout mice. A2AR agonists downregulate TLR-mediated TNF-α expression and upregulate VEGF expression in macrophages112. Similarly, another study suggested that adenosine upregulates VEGF in human macrophages via A2AR-mediated mechanisms113. The A1R mediates the release of VEGF from peripherally derived monocytes and promotes angiogenesis114. Adenosine increases the expression of thrombospondin-1 (TSP-1) in macrophages, resulting in stimulation of vascularization115. This effect depends on the A2AR and A2BR. Blockade of TSP-1 by an antibody counteracts the outgrowth of microvessels, suggesting a VEGF-independent mechanism of macrophage angiogenesis regulation by adenosine. Ramanathan et al.116 reported that A2AR agonists work in synergy with TLR agonists to enhance VEGF expression in macrophages. Individually added TLR or A2AR agonists failed to induce VEGF expression116. Given the crucial role of angiogenesis in tumor initiation, progression, invasion, and metastasis, targeting the adenosine signaling pathway to block the angiogenic function of TAMs may be a promising approach for immunotherapy.

Targeting adenosine signaling pathway for cancer therapy

Given the significant impact of the adenosine pathway in shaping the immunosuppressive TME, various therapeutic agents targeting this pathway are under investigation. Many drugs have been developed to target the CD39/CD73 and adenosine signaling pathways for cancer therapy, including small-molecule agonists, antagonists, and antibodies. Some of the drugs targeting CD39/CD73 and adenosine signaling are currently under clinical investigation (Table 1). Yan et al.61 reported inhibition of CD39 by an antibody reduces lung metastasis in an LWT1 lung cancer model via the P2X7/NLR family pyrin domain containing 3 (NALP3)/IL-18 axis. CD39 expression in myeloid cells is crucial for the effectiveness of anti-CD39 therapy in controlling metastasis61. The combination of anti-CD39 and anti-PD-1 therapy significantly extends survival in mice. An antibody targeting CD73 has been shown to amplify the cytotoxic effects of doxorubicin in triple-negative breast cancer cells. Suppression of cell migration and invasion was observed upon administration of an anti-CD73 antibody in in vitro experiments. CD73 antibody holds potential for development as an adjuvant therapy for triple-negative breast cancer140. Anti-CD73 therapy has also been shown to enhance the efficacy of immune checkpoint blockade therapy141. This effect is dependent on the presence of IFN-γ and CD8+ T cells. MDEI9447, an anti-CD47 monoclonal antibody, inhibits mouse syngeneic tumor growth and results in alterations in myeloid cells and lymphoid-infiltrating leukocytes, including CD8+ T cells and macrophages. The mechanisms underlying the antitumor function involves antibody-mediated CD73 internalization and inhibition of CD73 activity on tumor cells136. MEDI9447 relieves the adenosine-mediated immunosuppressive TME and combination with anti-PD1 therapy further enhances anti-tumor efficacy142. Perrot et al.119 reported that IPH5201 and IPH5301, which specifically target CD39 and CD73, respectively, block ATP hydrolysis into adenosine and consequently restore the function of T cells isolated from cancer patients. Furthermore, application of anti-CD39/CD73 therapy in combination with chemotherapy or immune checkpoint blockade therapy has shown promising results119. IPH5301 efficiently blocks CD73 enzyme activity because IPH5301 induces CD73 internalization compared to MEDI9447, thus being more active. A recent study suggested that anti-CD73 antibody treatment induces pro-inflammatory macrophage accumulation in tumors and improves the anti-tumor response143. Antibody treatment eliminates CD73-high tumor cells and reprogrammed the TME to assist in anti-tumor therapy. Takenaka et al.144 reported that AHR activation increases CD39 expression in TAMs and CD39 collaborates with CD73 to generate adenosine to suppress tumor-specific T cell immunity. Deletion of the CD39 coding gene, ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1), in myeloid cells slows tumor growth. This study highlighted that the TAM-induced increase in adenosine signaling may have a pivotal role in confining T cell immunity. Targeting CD39 in TAMs may synergize with T cell-based immunotherapy. SRF617, an investigational human IgG4 antibody, binds to human CD39 with a high affinity and effectively inhibits adenosine triphosphatase (ATPase) activity. In vitro experiments showed that SRF617 enhances T cell proliferation, DC maturation, and the release of IL-1β and IL-18 from macrophages. In a humanized CD39 knock-in mouse model, SRF617 penetrated the TME and increased CD8+ T cells in tumor118. TTX-030, a monoclonal antibody directed against CD39, is currently being evaluated in clinical trials as a potential therapy for cancer. TTX-030 inhibits CD39 ecto-ATPase activity through a non-competitive allosteric mechanism117. The anti-CD73 antibody, sym024, has demonstrated good tolerability across all dose levels as a single agent and in combination with PD-1 blockade. The most frequent treatment emergent adverse events were fatigue, nausea, diarrhea, dyspnea, and vomiting122. CPI-006, an anti-CD73 antibody, has been shown to have good safety and tolerability in a clinical study. Only a small portion of patients experienced grade 3 or 4 adverse events124. In a phase Ib-2 clinical study, the anti-CD73 antibody, oleclumab, was tested in patients with non-small cell lung cancer and has been shown to have acceptable tolerability. No dose-limiting toxicities, serious adverse events, or deaths occurred135.

View this table:
Table 1

Clinical investigations targeting CD39/CD73/adenosine signaling for cancer therapy

In addition to antibodies, many small-molecule inhibitors have been developed to target adenosine signaling pathways in cancer therapy. AB680 is a CD73 inhibitor that is currently being investigated in a phase I clinical trial to evaluate its safety and efficacy (NCT04104672). In a preclinical melanoma mouse model, AB680 suppressed CD73 in the TME and enhanced the anti-tumor effectiveness of PD-1 blockade132. AB680 restores T cell proliferation and enhances T cell cytokine production by reshaping the adenosine-induced immunosuppressive TME132,133. Namodenoson is an orally bioavailable, highly selective A3R agonist (Ki = 0.33 nM). In a phase II clinical trial, namodenoson was evaluated as a second-line therapy for advanced hepatocellular carcinoma. Although the primary endpoint of overall survival was not reached, the subgroup analysis of CPB7 patients revealed a trend towards enhanced overall survival and progression-free survival. Notably, a significant discrepancy was observed in the 12-month follow-up rates. Namodenoson demonstrated an excellent safety profile and presented encouraging efficacy signals in hepatocellular carcinoma with no treatment-related fatalities145. The A2AR/A2BR antagonist, AB928, enhanced chimeric antigen receptor (CAR) T cell therapy in colon carcinoma146. AB928 is now tested in several clinical trials in combination with anti-PD-1/programmed cell death ligand 1 (PD-L1) or CD73 antagonists for cancer therapy. Thus, targeting adenosine signaling in cancer therapy could open new and transformative pathways for developing innovative therapeutic approaches (Figure 4).

Figure 4
Figure 4

Targeting adenosine signaling pathways for cancer therapy. Many antibodies have been developed to block CD39/CD73 activity and suppress the production of adenosine. Some chemical antagonists have been developed to inhibit adenosine signaling in immune and tumor cells to block CD39/CD73 enzyme activity. Many inhibitors have been developed to counteract adenosine signaling in immune cells via A2AR/A2BR. Targeting the adenosine signaling pathway in the TME alleviates the immunosuppressive microenvironment and unleashes the anti-tumor potential of immune cells. ATP, adenosine triphosphate.

Conclusions and future perspectives

The adenosine signaling pathway, which is critical for modulating the TME and immune responses, is a valuable target for cancer therapy. As a key component of the TME, the function of TAMs is tightly regulated by adenosine. Targeting the adenosine signaling pathway within TAMs represents a promising strategy with significant potential for therapeutic advancement because of its pivotal role in shaping the TME. By inhibiting CD39/CD73-mediated adenosine production, local adenosine production can be reduced, potentially reversing the immunosuppressive TME and enhancing the infiltration of anti-tumor cells, such as T cells, into the tumor. The strategic targeting of CD39 and CD73 on TAMs could also synergize with other immunotherapies.

As our understanding of this pathway increases, more efficient cancer treatment strategies may be developed. Several key considerations are paramount for successful clinical translation of these therapies. First, a deeper understanding of the complex interactions between adenosine signaling and other pathways within the TME is crucial for the rational design of combination therapies. Second, the heterogeneity in AR expression and function across different tumor types and even within individual tumors may influence the efficacy of these therapies. Identifying patients most likely to derive the greatest benefit from targeting the adenosine pathway can help maximize clinical benefits while minimizing potential side effects. Third, the safety and tolerability of these agents must be carefully evaluated, particularly when considering the pleiotropic effects of adenosine on normal tissues. Although some studies have reported favorable safety profiles for adenosine pathway inhibitors, long-term follow-up and large-scale clinical trials are warranted to fully understand the risks associated with these treatments.

Conflict of interest statement

No potential conflicts of interest are disclosed.

Author contributions

Conceived and revised the review: Li Yang, Yi Zhang.

Wrote the paper: Lei Yang.

  • Received June 24, 2024.
  • Accepted November 4, 2024.

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