In the context of acute myeloid leukemia (AML), macrophage polarization plays a pivotal role in disease progression and therapeutic resistance. The tumor microenvironment in AML is characterized by a predominance of tumor-associated macrophages skewed towards the M2 phenotype, which fosters an immunosuppressive milieu conducive to leukemia cell survival and immune evasion [33, 61, 62–63]. M2 macrophages are induced by cytokines such as IL-10, TGF-β, and CSF-1, which activate signaling pathways like STAT3 and STAT6, promoting angiogenesis, tissue repair, and immunosuppression [40, 64, 65]. These M2 macrophages secrete pro-angiogenic factors like VEGF, facilitating the formation of new blood vessels that supply nutrients and oxygen to leukemia cells, thereby enhancing their growth and survival [66, 67–68]. Moreover, M2 macrophages contribute to chemoresistance by releasing anti-inflammatory cytokines and growth factors that protect leukemia stem cells from apoptosis, particularly within the protective bone marrow niche [61, 69, 70, 71, 72–73]. In contrast, pro-inflammatory M1 macrophages, though less prevalent in the AML TME, have the potential to exert anti-leukemic effects by producing cytokines like IL-12 and TNF-α, which stimulate cytotoxic T cells and natural killer cells [39, 62, 63, 66]. However, the AML microenvironment often inhibits M1 polarization, limiting anti-tumor immunity [62, 63, 74, 75]. Therapeutic strategies targeting macrophage polarization in AML are gaining traction, with approaches such as blocking the CSF-1/CSF-1R signaling pathway or inhibiting IL-10 and TGF-β to reprogram M2 macrophages towards an M1 phenotype [61, 64, 65, 76]. These strategies aim to shift the TME towards a more pro-inflammatory, anti-tumor state, potentially enhancing the efficacy of existing AML therapies and reducing the risk of relapse [65, 74, 76, 77]. Understanding the dynamic interplay between macrophage polarization and the AML microenvironment is crucial for developing effective therapeutic interventions that can disrupt the supportive niche for leukemia cells and restore anti-tumor immunity.

Macrophage polarization plays a pivotal role in shaping the tumor microenvironment of acute lymphoblastic leukemia, influencing disease progression, immune evasion, and therapeutic resistance. In ALL, bone marrow-derived macrophages are reprogrammed into leukemia-associated macrophages (LAMs), which predominantly exhibit an M2-like polarization phenotype characterized by immunosuppressive and pro-tumor functions [33, 59, 78]. These LAMs secrete cytokines such as IL-10 and TGF-β, fostering an immunosuppressive TME that dampens cytotoxic T-cell activity and supports leukemia cell survival [37, 79, 80, 81–82]. Notably, aberrant metabolic pathways in ALL cells, including dysregulated lipid and amino acid metabolism, have been implicated in skewing macrophage polarization toward the M2 phenotype, further perpetuating leukemia growth and chemoresistance [22, 83]. Clinical studies highlight the correlation between M2-polarized macrophages and poor prognosis in ALL. For instance, M2-like LAMs promote angiogenesis and stromal remodeling, facilitating leukemia cell proliferation and infiltration into protective niches [13, 33, 62, 84]. Additionally, interactions between ALL blasts and macrophages via CSF-1/CSF-1R signaling sustain M2 polarization, creating a feedforward loop that enhances leukemia cell survival and reduces sensitivity to conventional therapies [65, 85, 86, 87, 88–89]. Emerging evidence also underscores the role of immune checkpoint molecules like Tim-3 in mediating M2 polarization-driven immune escape. In benzene-induced leukemia models, Tim-3 overexpression on macrophages correlates with M2 polarization and AML progression, suggesting analogous mechanisms may operate in ALL [40, 82].

In chronic leukemia, macrophage polarization plays a pivotal role in disease progression, immune evasion, and therapeutic resistance. Tumor-associated macrophages in chronic lymphocytic leukemia and chronic myeloid leukemiapredominantly exhibit an M2-like phenotype, characterized by anti-inflammatory and pro-tumorigenic functions [13, 33]. These M2 macrophages secrete cytokines such as IL-10 and TGF-β, which suppress cytotoxic T-cell and natural killer (NK) cell activity, creating an immunosuppressive microenvironment that facilitates leukemic cell survival and proliferation [13, 90]. In CLL, M2 macrophages within the bone marrow and lymphoid organs promote angiogenesis through the secretion of vascular endothelial growth factor (VEGF) [91] and support leukemic cell survival by releasing survival factors like IL-6 [92]. Similarly, in CML, M2 TAMs contribute to disease progression by supporting leukemic stem cells [93, 94] and conferring resistance to tyrosine kinase inhibitors (TKIs) such as imatinib [93, 95] (Table 1). The interaction between M2 macrophages and leukemic cells is mediated by complex signaling pathways, including STAT3, STAT6, and PI3K/AKT, which enhance leukemic cell survival and protect them from immune-mediated destruction [61, 90, 144, 145].

Macrophage polarization plays a pivotal role in the progression and therapeutic resistance of lymphoma, a heterogeneous group of hematological malignancies. Within the tumor microenvironment, macrophages exhibit remarkable plasticity, polarizing into either pro-inflammatory M1 or anti-inflammatory M2 phenotypes [31, 146, 147]. In lymphoma, the TME is often dominated by M2-polarized tumor-associated macrophages, which contribute to tumor progression, immune evasion, and chemotherapy resistance [13, 148, 149]. M2 macrophages are induced by cytokines such as IL-4, IL-10, and IL-13 [150, 151], and are characterized by the secretion of anti-inflammatory cytokines like IL-10 and TGF-β, which suppress cytotoxic immune responses and promote tumor cell survival [152, 153]. Additionally, M2 TAMs support angiogenesis through the secretion of VEGF [150, 154] and facilitate extracellular matrix remodeling, fostering a conducive environment for tumor growth and metastasis [6, 13]. The M2-to-M1 macrophage ratio within the TME is a critical determinant of lymphoma outcomes, with a higher M2 prevalence correlating with more aggressive disease, poorer prognosis, and resistance to conventional therapies [148, 149, 155]. M2 macrophages also interact with stromal cells to release survival factors such as CCL2 and CXCL12, which activate pro-survival signaling pathways like PI3K/AKT and STAT3 in lymphoma cells [148, 156], further enhancing chemoresistance. Therapeutic strategies targeting macrophage polarization, such as reprogramming M2 TAMs to an M1 phenotype [147, 157, 158] or inhibiting key signaling pathways like CSF-1/CSF-1R [76, 87, 159], hold promise in reshaping the TME to favor anti-tumor immunity. Approaches including TLR agonists [157, 160], CSF-1R inhibitors [76, 87], and CD47 blockade [155] are being explored to enhance macrophage-mediated phagocytosis and restore immune surveillance. By modulating macrophage polarization, these interventions aim to disrupt the supportive niche for lymphoma cells, enhance chemotherapy efficacy, and improve patient outcomes [6, 157, 161]. Continued research into the dynamic interplay between macrophage polarization and the TME is essential for developing novel therapeutic strategies to combat lymphoma progression and resistance [162].

Multiple myeloma (MM), a plasma cell malignancy and the second most common hematologic cancer, is characterized by complex interactions between myeloma cells and the immunosuppressive tumor microenvironment [152]. Tumor-associated macrophages, particularly those polarized toward the M2 phenotype, play a pivotal role in promoting MM progression, therapy resistance, and immune evasion [163, 164–165]. Bone marrow (BM)-infiltrating M2 macrophages are recruited and educated by myeloma-secreted factors, such as CCL3 and IL-10 [152, 166], which activate pro-tumor signaling pathways, including PI3K/AKT/RhoA [166, 167] and JAK/STAT3 [168], to sustain immunosuppression and tumor survival. These M2-polarized TAMs enhance myeloma proliferation, inhibit apoptosis, and confer resistance to proteasome inhibitors like Bortezomib by creating a protective niche [163, 169]. For instance, myeloma-derived CCL3 binds CCR5 on macrophages, driving M2 polarization and suppressing drug sensitivity [166, 169], while CCR5 antagonist Maraviroc (MVC) reverses this effect, restoring Bortezomib efficacy in preclinical models.

IL-10 further amplifies M2 polarization [13, 152], fostering a TME rich in immunosuppressive cytokines and stromal interactions that shield myeloma cells from chemotherapy [170]. Notably, IL-32, overexpressed in MM patients, induces macrophage-mediated drug resistance by enhancing immunosuppressive functions and adhesion molecule expression (no direct citation in provided documents; omitted). M2 macrophages also secrete factors that sustain myeloma stemness and bone destruction, exacerbating disease aggressiveness [171]. Conversely, targeting macrophage polarization—via CCR5 inhibition [166], IL-10/IL-32 blockade, or epigenetic modulation of histone lactylation-disrupts pro-tumor signaling and re-sensitizes myeloma cells to therapy [172].

Clinical evidence underscores the prognostic significance of M2 polarization markers in MM, with elevated CCL3/CCR5 [166, 169] and M2-associated genes correlating with advanced disease and poor outcomes [13, 173]. Emerging strategies to reprogram TAMs toward an anti-tumor M1 phenotype [174, 175] or deplete M2 subsets hold therapeutic promise, though challenges remain in achieving durable responses [2, 149].

The selective elimination of M2-polarized macrophages emerges as a promising therapeutic approach in hematologic malignancies, given their pivotal role in facilitating tumor progression, mediating immune evasion, and conferring treatment resistance. M2 macrophages, often referred to as tumor-associated macrophages, create an immunosuppressive tumor microenvironment that supports leukemia, lymphoma, and myeloma cell survival [13, 188, 189]. Therapeutic approaches aimed at depleting or reprogramming M2 macrophages can shift the TME toward a pro-inflammatory, anti-tumor state, enhancing the efficacy of existing treatments [2, 6, 165]. One effective strategy for targeting M2 macrophages is their selective depletion. Clodronate liposomes have been widely used to deplete macrophages, including M2 TAMs, in preclinical models. Clodronate, a bisphosphonate, induces apoptosis in macrophages upon intracellular accumulation. Studies have shown that clodronate liposome treatment reduces M2 macrophage populations, decreases immunosuppressive cytokines, and promotes cytotoxic T-cell infiltration, thereby enhancing anti-tumor immunity and improving chemotherapy efficacy [74, 190, 191]. This approach disrupts the supportive niche for leukemia cells and shifts the TME toward an M1-dominant phenotype, which is critical for anti-tumor responses [165, 192]. Another promising strategy involves targeting specific M2 macrophage markers, such as CD163 and CD206. These surface markers are highly expressed on M2 macrophages and are associated with their immunosuppressive and pro-tumorigenic functions [192, 193–194]. Monoclonal antibodies against CD163 and CD206 have been developed to selectively deplete or inhibit M2 macrophages. For example, anti-CD163 antibodies have shown efficacy in inducing TAM apoptosis and reducing tumor growth in preclinical models [14, 194]. Additionally, small-molecule inhibitors targeting signaling pathways that sustain M2 polarization, such as the CSF-1R pathway, have demonstrated potential in reducing M2 macrophage populations and enhancing anti-tumor immunity [14, 65, 195]. Inhibition of key signaling pathways that drive M2 polarization is another therapeutic avenue. The CCL2/CCR2 axis, which recruits monocytes to the TME and promotes their differentiation into M2 macrophages, has been targeted to disrupt this process [196, 197]. Blocking CCL2/CCR2 signaling reduces M2 macrophage infiltration and shifts the TME toward an M1 phenotype, enhancing anti-tumor immunity and chemotherapy sensitivity [196, 198]. Similarly, CSF-1R inhibitors, such as pexidartinib, have shown efficacy in reducing M2 macrophage populations and reprogramming the TME to support anti-tumor responses [65, 195, 199] (Table 1). Reprogramming M2 macrophages toward an M1 phenotype is an emerging strategy. TLR agonists, such as TLR4 and TLR9 agonists, have been shown to induce M1 polarization, enhancing pro-inflammatory cytokine production and phagocytic activity against tumor cells [200, 201]. Additionally, small-molecule drugs targeting metabolic pathways, such as PI3K-γ inhibitors, have demonstrated potential in shifting macrophage polarization from M2 to M1, thereby reducing immunosuppression and enhancing anti-tumor immunity [192, 195, 202].

Targeting M2 macrophages through depletion, inhibition of specific markers, or reprogramming offers a promising approach to overcoming therapy resistance in blood cancers. These strategies aim to disrupt the immunosuppressive TME, enhance anti-tumor immunity, and improve the efficacy of conventional therapies [2, 24, 188]. Continued research into the mechanisms of macrophage polarization and the development of targeted therapies will be essential for translating these approaches into clinical practice [6, 191, 203].

Macrophage polarization is another promising therapeutic strategy in leukemia, aiming to disrupt the tumor-supporting microenvironment and enhance anti-tumor immunity. M2-polarized tumor-associated macrophages play a critical role in promoting leukemia progression by creating an immunosuppressive tumor microenvironment that supports leukemic cell survival, immune evasion, and chemotherapy resistance [13, 72]. Strategies to inhibit M2 polarization include blocking key signaling pathways such as CCL2/CCR2 and CSF1R [204, 205–206], as well as directly depleting M2 macrophages using agents like clodronate liposomes 8 or targeting surface markers such as CD163 and CD206 [192, 207]. These approaches aim to shift the TME towards a pro-inflammatory, anti-tumor state, thereby improving treatment outcomes.

One effective strategy involves blocking the CCL2/CCR2 pathway, which is crucial for the recruitment and polarization of monocytes into M2-like TAMs [204, 205]. CCL2, also known as monocyte chemoattractant protein-1 (MCP-1), binds to its receptor CCR2 on monocytes, facilitating their migration into the TME where they differentiate into M2 macrophages [205, 208]. Inhibition of this axis disrupts the recruitment and polarization process, reducing the infiltration of M2 macrophages and their immunosuppressive influence. Preclinical studies have demonstrated that blocking CCL2/CCR2 shifts macrophage populations from the M2 to the M1 phenotype [165, 204], enhancing anti-tumor immunity and creating a more hostile environment for leukemia cells. This shift is associated with decreased levels of immunosuppressive cytokines like IL-10 and TGF-β and increased levels of pro-inflammatory cytokines such as IL-12 [209, 210], further supporting the M1 phenotype. Additionally, CCL2/CCR2 inhibition reduces angiogenesis and tumor cell proliferation [72, 153], processes in which M2 TAMs play a significant role, thereby enhancing the effectiveness of conventional chemotherapeutic agents.

Another promising approach is the use of CSF1R inhibitors, which target the colony-stimulating factor 1 receptor (CSF1R) pathway essential for the recruitment, survival, and maintenance of M2 macrophages [13, 206]. CSF1R inhibitors, such as pexidartinib, have shown efficacy in reducing M2 macrophage populations and their pro-tumoral effects in various malignancies, including leukemia [211]. By blocking CSF1R, these inhibitors diminish the recruitment and polarization of macrophages towards the M2 phenotype [206, 211], shifting the TME towards a more anti-tumorigenic state. Studies have shown that CSF1R inhibition leads to a decrease in immunosuppressive cytokines and an increase in pro-inflammatory cytokines [209, 212], enhancing anti-tumor immune responses. Furthermore, CSF1R inhibitors have demonstrated synergistic effects when combined with chemotherapy [74, 213], improving leukemia cell sensitivity to treatment by reactivating anti-tumor immunity and reducing TAM-mediated protection. CSF1R inhibition also reduces angiogenesis and stromal support for leukemia cells [153, 161], limiting nutrient and oxygen supply and weakening the supportive TME.

Inducing macrophage reprogramming to shift tumor-associated macrophages from an immunosuppressive M2 phenotype to a pro-inflammatory M1 phenotype represents a cutting-edge therapeutic strategy in blood cancer, particularly leukemia. This approach aims to remodel the tumor microenvironment, enhance anti-tumor immunity, and overcome chemotherapy resistance. M2-polarized TAMs are key contributors to leukemia progression, fostering immune evasion, angiogenesis, and chemoresistance through the secretion of immunosuppressive cytokines such as IL-10 and TGF-β [147, 201, 214]. Reprogramming these macrophages to an M1 phenotype can disrupt leukemia-supportive pathways, promote phagocytic activity, and sensitize leukemia cells to conventional therapies [14, 25, 215]. Emerging evidence highlights the potential of TLR agonists, small molecule drugs, and other agents in achieving this phenotypic shift, offering new avenues for therapeutic intervention [157, 216, 217].

TLR agonists have emerged as a potent tool for macrophage reprogramming in leukemia. TLRs, which recognize pathogen-associated molecular patterns (PAMPs), play a critical role in innate immunity and macrophage polarization. TLR agonists, such as TLR7/8 agonists (e.g., imiquimod and resiquimod) [218], TLR4 agonists [216], and TLR9 agonists, have demonstrated the ability to shift M2 macrophages toward an M1 phenotype [217] (Table 1). This reprogramming is mediated through the activation of signaling pathways that induce the production of pro-inflammatory cytokines (e.g., TNF-α, IL-12) and enhance phagocytic and antigen-presenting functions [216, 218]. Preclinical studies have shown that TLR4 and TLR9 agonists significantly reduce M2 TAM populations in leukemia models, creating a more inflammatory and anti-tumor TME [216, 217]. Furthermore, combining TLR agonists with chemotherapy has shown synergistic effects, as TLR-mediated reprogramming disrupts the protective niche provided by M2 macrophages and sensitizes leukemia cells to cytotoxic agents [201, 219]. TLR agonists also activate other immune cells, such as dendritic cells and natural killer cells, amplifying the overall anti-leukemia immune response [157, 217]. Ongoing clinical trials are exploring optimized delivery systems and combination therapies to maximize the therapeutic potential of TLR agonists while minimizing immune-related toxicities [175, 220].

Small molecule drugs offer another promising approach to macrophage reprogramming by targeting specific signaling pathways involved in macrophage polarization. PI3K-γ inhibitors, such as IPI-549, have shown efficacy in shifting macrophages from an M2 to an M1 phenotype [6, 221]. PI3K-γ is a key regulator of immune cell responses, and its inhibition reduces the production of immunosuppressive cytokines while enhancing T-cell-mediated anti-leukemia activity [6]. Similarly, JAK inhibitors, which block the JAK/STAT pathway, inhibit M2 polarization by disrupting IL-4 and IL-13 signaling [56, 147]. This mechanism reduces the recruitment and polarization of M2 macrophages, reshaping the TME to be more hostile to leukemia cells [65, 222]. Bromodomain and extra-terminal domain (BET) inhibitors represent another class of small molecules with potential in macrophage reprogramming. BET inhibitors disrupt chromatin remodeling, leading to the downregulation of M2-related genes and an increase in M1 polarization and inflammatory responses within the TME [223, 224]. These small molecule approaches not only alter macrophage behavior but also weaken the protective niche exploited by leukemia cells, making them more susceptible to chemotherapy [201, 214]. Ongoing research is focused on identifying optimal drug combinations and delivery methods to enhance therapeutic efficacy and minimize adverse effects [157, 225].

In addition to TLR agonists and small molecule drugs, cytokines such as IFN-γ have demonstrated potential in macrophage reprogramming. IFN-γ promotes M1 polarization by activating STAT1 signaling, leading to the production of pro-inflammatory cytokines and enhanced phagocytic activity [147, 226]. Combining cytokines with other reprogramming agents may further enhance their efficacy in reshaping the TME [227, 228]. Other agents, such as CD40 agonists, have also shown promise in preclinical studies by activating macrophages and promoting anti-tumor immunity [157, 229]. These approaches highlight the versatility of macrophage reprogramming strategies and their potential to complement existing leukemia therapies [230].

Enhancing macrophage antitumor activity by modulating polarization states represents a transformative therapeutic strategy in leukemia, leveraging mechanisms such as CD47-SIRPα axis blockade, phagocytosis potentiation, and microenvironment reprogramming to reverse immunosuppressive LAM phenotypes and restore tumoricidal M1-like functions.

Targeting the CD47-SIRPα Phagocytic Checkpoint The CD47-SIRPα axis is a critical immune evasion pathway exploited by leukemia cells, where CD47 overexpression on malignant cells binds to SIRPα on macrophages, transmitting a "don’t eat me" signal to inhibit phagocytosis [231, 232]. Preclinical studies demonstrate that blocking this axis via anti-CD47 antibodies (e.g., magrolimab) or SIRPα antagonists disrupts this interaction, significantly enhancing macrophage-mediated clearance of leukemia cells [233, 234] (Table 1). For example, IL-4 treatment in murine models enhances macrophage phagocytosis of leukemia cells by downregulating CD47-SIRPα signaling while upregulating pro-phagocytic ligands like calreticulin [235]. Additionally, engineered chimeric antigen receptor macrophages (CAR-Ms) targeting CD47 synergize with opsonizing antibodies to amplify phagocytic activity, as shown in non-small cell lung cancer models [236, 237] (Table 1). Clinical trials combining CD47 blockade with azacitidine or rituximab have shown efficacy in myeloid malignancies, underscoring its translational potential [74, 233].

Reprogramming Macrophage Polarization to Proinflammatory States Leukemia-associated macrophages predominantly exhibit M2-like polarization, promoting immune suppression and chemoresistance [13, 153]. Reversing this phenotype to proinflammatory M1-like states is pivotal for restoring antitumor immunity. HDAC6 inhibitors (e.g., Nexturastat A) reprogram macrophages by suppressing STAT3/IL-10 signaling, enhancing M1 polarization, and synergizing with anti-CD47 therapy to improve phagocytosis and NK cell activation in melanoma models [238]. Similarly, PPARδ antagonists (e.g., GSK0660) downregulate CD47 expression in leukemia cells while promoting macrophage M1 polarization via NF-κB activation [239]. In AML, Tim-3 inhibition disrupts M2 polarization pathways, restoring phagocytic capacity and T-cell activation [72]. These approaches highlight the dual benefit of polarization modulation: directly enhancing tumor cell clearance while remodeling the immunosuppressive leukemia microenvironment.

Combination Therapies and Future Directions Emerging strategies integrate CD47-SIRPα blockade with polarization modifiers or cytotoxic therapies to overcome resistance. For instance, HDAC6 inhibitors enhance the efficacy of anti-CD47 antibodies in vivo by increasing macrophage infiltration and M1 polarization in melanoma [238]. In glioma, CD47 blockade post-resection prevents residual cell immune escape by sustaining phagocytic activity [240]. CAR-M therapies, engineered to express CD47-blocking scFvs, further demonstrate enhanced tumor targeting and phagocytosis in solid tumors, with potential applicability in leukemia [236, 237]. Additionally, CSF-1R inhibitors (e.g., PLX3397) deplete protumoral M2 macrophages, while IL-4/IL-13 pathway agonists promote M1 polarization, offering combinatory avenues [230]. Future studies should prioritize biomarkers for polarization states (e.g., CD86/CD163 ratios) and optimize spatial–temporal delivery of polarization modulators to minimize toxicity.

Translational Implications and Clinical Challenges Despite promising preclinical data, clinical translation faces hurdles, including on-target anemia from CD47 blockade and cytokine release syndrome from CAR-M therapies [233, 236]. Next-generation agents like SIRPα-Fc fusion proteins (e.g., TTI-621) exhibit reduced erythrocyte binding while maintaining phagocytic enhancement in gastric cancer models [241] (Table 1). Similarly, dual-targeting agents blocking CD47 and PD-L1/CTLA-4 may amplify immune activation while mitigating toxicity [242]. In AML, macrophage depletion via clodronate liposomes abrogates IL-4-induced antileukemic effects, emphasizing the need for precision in macrophage-targeted therapies [74]. Longitudinal studies monitoring macrophage plasticity and microenvironmental crosstalk will be critical to refine these strategies.