Natural killer cells, macrophages and dendritic cells as innate immune therapies for blood cancers.

Introduction

The immune system plays a central role in protecting the host against both infectious agents and malignant transformation. This defense relies on coordinated interactions between innate and adaptive immune components that together determine whether abnormal cells are eliminated or allowed to persist. Innate immunity represents the first line of defense and is characterized by rapid, antigen-independent responses that are particularly relevant during the early stages of tumor development. Among innate immune cells, natural killer (NK) cells, macrophages, and dendritic cells (DCs) have emerged as key regulators of cancer immunosurveillance and therapeutic response [ 1 , 2 ].

For many years, cancer immunotherapy has focused predominantly on adaptive immune mechanisms, particularly T cell–mediated responses, which have led to major therapeutic advances. However, the inherent capabilities of innate immune cells, which include their antigen-independent recognition of malignant cells, swift effector functions, and a generally favorable safety profile with reduced off-target toxicities, position them as highly attractive targets for novel therapeutic interventions, especially within the context of hematological malignancies [ 1 , 3 ]. The rapid and non-specific nature of innate immunity confers a distinct advantage in the initial control of tumor progression compared to the comparatively slower, antigen-specific responses characteristic of adaptive immunity. This inherent speed and broad recognition suggest that harnessing innate immune cells could provide a quicker therapeutic onset, a particularly critical factor in the management of aggressive blood cancers where rapid intervention can significantly impact patient outcomes [ 4 ].

Despite their intrinsic potency, tumors have evolved sophisticated strategies to suppress immune responses, leading to pervasive immune evasion [ 1 ]. The development of complex signaling pathways by tumors to subvert immune surveillance highlights a fundamental challenge: even the most potent innate immune cells face a formidable battle against an immunosuppressive tumor microenvironment (TME). This necessitates therapeutic strategies that extend beyond mere activation of innate cells; they must also actively counteract the TME-mediated suppression to ensure sustained and effective anti-tumor responses [ 5 ]. This comprehensive review will delve into the fundamental biology of NK cells, macrophages, and DCs, explore their current applications in the immunotherapy of blood cancers, critically assess the challenges encountered during [ 6 ]clinical translation, and illuminate innovative strategies aimed at enhancing their anti-tumor efficacy [ 7 ]. To strengthen coverage of recent advances, we updated the NK cell sections using a structured PubMed search combining terms related to NK cell therapy, hematological malignancies, CAR-NK cells, and tumor microenvironment–mediated immune suppression, with emphasis on clinically relevant studies and major mechanistic reviews [ 8 – 11 ].

Natural killer (NK) cell-based immunotherapies for blood cancers

Fundamental anti-tumor mechanisms of NK cells

Natural Killer (NK) cells are circulating innate lymphocytes endowed with the remarkable ability to directly eliminate metastatic cancer cells without requiring prior activation by antigen-presenting cells [ 1 ]. Their discovery in the 1970s stemmed from their spontaneous reactivity against tumor cells [ 12 , 13 ]. The cytotoxic prowess of NK cells is meticulously regulated by a delicate balance between activating and inhibitory receptors expressed on their surface [ 1 ]. Upon engagement with target cells, NK cells unleash their cytotoxic potential by releasing granules containing perforin and granzymes, which induce target cell death [ 12 , 14 ].

An important mechanism of NK cell-mediated anti-tumor activity is the “missing self” recognition mechanism. Through this process, NK cells efficiently detect and rapidly destroy tumor cells that have downregulated their Major Histocompatibility Complex class I (MHC-I) expression [ 1 , 15 ]. This mechanism is particularly relevant for blood cancers, as malignant cells frequently downregulate MHC-I as a strategy to evade detection and elimination by cytotoxic T lymphocytes. NK cells are uniquely equipped to target a common immune evasion strategy employed by cancer, rendering them invaluable in scenarios where T-cell responses might be compromised due to antigen presentation issues [ 16 ]. Beyond their direct cytotoxic capabilities, NK cells function as crucial orchestrators of broader immune responses. They secrete a repertoire of cytokines, including interferon-gamma (IFNγ), tumor necrosis factor-alpha (TNFα), and granulocyte-macrophage colony-stimulating factor (GM-CSF), along with various chemokines [ 17 ]. These soluble mediators serve to activate other immune cells, such as T and B cells, thereby amplifying and boosting adaptive immunity [ 1 , 18 ]. Furthermore, a fascinating aspect of NK cell biology is the existence of a subgroup that can exhibit memory-like recall responses, blurring the traditional distinctions between innate and adaptive immunity [ 1 , 19 ]. Their inherent ability to circulate extensively within the blood and lymphatic streams empowers NK cells to effectively contain hematological malignancies and control metastatic dissemination throughout the body [ 12 , 20 , 21 ]. In addition to direct recognition of malignant cells, NK cells play a central role in mediating the therapeutic effects of antibody-based immunotherapies through Fc receptor–dependent mechanisms.

Monoclonal antibodies, antibody-dependent cellular cytotoxicity (ADCC), and NK cell engagers in blood cancers

Monoclonal antibodies (mAbs) represent one of the earliest and most successful forms of cancer immunotherapy and remain a cornerstone of treatment for several hematological malignancies. A major mechanism underlying their clinical efficacy is antibody-dependent cellular cytotoxicity (ADCC), a process primarily mediated by NK cells through engagement of the Fc receptor CD16 (FcγRIIIa). Upon binding of the antibody Fc region to CD16, NK cells become activated and induce targeted killing of antibody-coated malignant cells through the release of cytotoxic granules and pro-inflammatory cytokines [ 22 , 23 ].

In B-cell malignancies, anti-CD20 monoclonal antibodies such as rituximab, obinutuzumab, and ofatumumab are widely used in the treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphomas. Their therapeutic activity relies not only on direct signaling effects but also on efficient recruitment of NK cells to mediate ADCC, which has been shown to correlate with clinical response [ 12 , 20 – 23 ]. Similarly, in multiple myeloma, the anti-SLAMF7 monoclonal antibody elotuzumab is approved for clinical use and exerts its anti-myeloma activity largely through NK cell activation and ADCC, highlighting the central role of NK cells in antibody-based immunotherapy [ 12 , 20 , 21 ].

Beyond conventional monoclonal antibodies, next-generation NK cell–engaging platforms have been developed to further enhance ADCC. Bispecific killer cell engagers (BiKEs) are engineered molecules that simultaneously bind CD16 on NK cells and tumor-associated antigens on malignant cells, thereby promoting targeted NK cell activation. Trispecific killer cell engagers (TriKEs) extend this concept by incorporating an additional stimulatory component, often interleukin-15 (IL-15), to enhance NK cell proliferation, persistence, and cytotoxic function. Early preclinical and clinical studies have demonstrated that BiKEs and TriKEs can significantly augment NK cell–mediated anti-tumor responses in hematological malignancies, including acute myeloid leukemia and multiple myeloma, offering a promising bridge between antibody therapy and adoptive NK cell approaches [ 24 – 26 ].

Collectively, monoclonal antibodies, BiKEs, and TriKEs underscore the therapeutic relevance of endogenous NK cells and highlight how NK cell–mediated cytotoxicity can be effectively harnessed without the need for cellular infusion. These strategies complement adoptive NK cell transfer and CAR-NK therapies and provide flexible, off-the-shelf immunotherapeutic options for patients with blood cancers.

Adoptive NK cell transfer strategies and clinical outcomes

Recent leukemia-focused syntheses summarize the major NK therapeutic modalities across leukemia subtypes and highlight key translational barriers, including persistence, trafficking, and leukemic immune evasion [ 9 , 27 ]. Clinical investigations have explored diverse sources of NK cells for ACT, including ex vivo expanded NK cell lines (e.g., NK-92), peripheral blood-derived NK cells, and umbilical cord blood-derived NK cells [ 27 , 28 ]. These therapeutic approaches have demonstrated varying degrees of efficacy, ranging from transient anti-leukemia activity to sustained remission in carefully selected patient cohorts [ 27 , 29 ]. A significant advantage of NK cell ACT lies in its generally favorable safety profile, characterized by a minimal incidence of severe adverse effects such as cytokine release syndrome (CRS) or graft-versus-host disease (GVHD) [ 30 ]. For instance, a Phase 1 clinical trial evaluating “off-the-shelf” activated NK cells (aNK) in patients with refractory/relapsed AML reported no dose-limiting toxicities or any grade 3–4 toxicities definitively related to aNK cell infusions [ 31 , 32 ].

Chimeric antigen receptor (CAR)-NK cell advancements and their unique advantages

Building upon the success of T cell engineering, NK cells can also be genetically modified with Chimeric Antigen Receptors (CARs) to precisely direct their specificity towards malignant cells [ 30 ]. CAR-NK cells present several unique advantages over their CAR-T cell counterparts. They may exhibit reduced sensitivity to tumor escape mechanisms caused by CAR antigen loss, primarily because they retain their intrinsic CAR-independent cytotoxicity [ 30 , 33 ]. Furthermore, CAR-NK cells demonstrate a significantly reduced risk of cytokine release syndrome (CRS). This improved safety profile is directly attributable to the intrinsic biology of NK cells, which secrete substantially lower levels of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, and IL-10, upon engaging with target cells compared to T cells [ 30 , 34 ]. This causal link implies that CAR-NK therapies could offer a significantly safer and more tolerable treatment profile, potentially broadening their applicability to a wider patient population, including those who may be less tolerant of the high-grade toxicities sometimes associated with CAR-T cell therapies [ 35 ]. This favorable safety profile may allow CAR-NK cells to be combined with other immunotherapeutic or cytotoxic agents that are difficult to administer alongside CAR-T cells [ 35 , 36 ]. Early clinical data in CD19-positive B-cell malignancies support the feasibility of cord blood–derived CAR-NK cells, including encouraging response rates and a low incidence of major toxic effects such as severe CRS or neurotoxicity [ 30 , 37 ]. Additionally, CAR-NK cells may mitigate on-target, off-tumor side effects, such as bone marrow suppression, which can occur with some CAR-T cell therapies that target antigens also expressed on hematopoietic stem cells (e.g., CD33) [ 38 ]. Current research is intensely focused on strategies to enhance CAR-NK cell persistence, broaden their therapeutic targets, and refine manufacturing processes to improve accessibility and scalability [ 30 , 39 , 40 ] (Fig. 1 ). Fig. 1 Overview of NK cell–based immunotherapy strategies in blood cancers. ( A ) Adoptive NK cell transfer: NK cells derived from peripheral blood, umbilical cord blood, or NK cell lines are expanded and activated ex vivo using cytokines and growth factors prior to infusion to target malignant cells. ( B ) CAR-NK cells: NK cells are genetically engineered to express a chimeric antigen receptor (CAR), enhancing tumor specificity while retaining native NK receptor–mediated cytotoxicity. ( C ) Key advantages of CAR-NK therapy compared with CAR-T therapy: CAR-NK cells have demonstrated a lower incidence of severe cytokine release syndrome (CRS) and neurotoxicity in early clinical studies and may reduce antigen-escape risk through CAR-independent killing mechanisms

Challenges in NK cell therapy: Persistence, homing, and tumor microenvironment resistance

Despite the encouraging clinical outcomes, persistent challenges continue to limit the widespread efficacy of NK cell-based therapies. These include limited NK cell persistence in vivo, the potential for disease relapse, and considerable heterogeneity in patient responses [ 27 ]. The therapeutic effectiveness of NK cell infusion, particularly against solid tumors, is significantly hampered by inadequate tumor infiltration and insufficient persistence and activation within the complex tumor microenvironment (TME) [ 41 ].

The TME presents a formidable array of barriers that causally contribute to NK cell dysfunction and impaired activity. Recent work has detailed how the tumor microenvironment suppresses NK-cell metabolism, trafficking, and receptor signaling, contributing to reduced cytotoxicity and impaired persistence. In addition to soluble mediators such as TGF-β and adenosine, suppressive myeloid populations and chronic stimulation can drive dysfunctional NK phenotypes within tumors and leukemic niches, emphasizing that overcoming microenvironmental suppression is central to effective NK-based immunotherapy [ 6 , 8 , 10 ]. These include: Metabolic features: Hypoxia, elevated levels of adenosine, reactive oxygen species (ROS), and prostaglandins negatively impact NK cell activity and survival [ 37 , 41 ]. Cellular components: Cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) actively suppress NK cell-dependent anti-cancer immunity [ 41 , 42 ].

The various TME factors, both metabolic and cellular, actively suppress NK cell function. This indicates that simply infusing NK cells, even highly potent ones, may be insufficient if the TME remains hostile. Therefore, future therapeutic strategies must not only enhance the intrinsic properties of NK cells, such as their persistence and homing capabilities, but also actively modulate or “reprogram” the TME to establish a more permissive environment conducive to sustained NK cell function [ 43 , 44 ]. This underscores the critical need for multi-pronged approaches that combine cell therapy with TME-targeting agents. In myeloid leukemia (ML), NK cells frequently exhibit more severe functional exhaustion compared to T cells, characterized by impaired cytotoxicity, reduced cytokine production, and diminished proliferative capacity, further highlighting the impact of the TME on NK cell efficacy [ 45 ].

Strategies to enhance NK cell cytotoxic activity and clinical efficacy

To overcome the existing limitations, novel protocols are being developed to enhance NK cell expansion and persistence [ 45 ]. Strategies aimed at improving NK cell cytotoxicity ex vivo include treatment with various cytokines, such as interleukin (IL)-15, IL-2, or a combination of IL-12, IL-15, and IL-18 [ 24 , 25 ]. The use of feeder cell lines, including K562, RPMI8866, or EBV-LCL, often genetically altered to express specific factors, also serves to boost NK cell expansion and activation [ 24 , 26 ].

Enhancing the homing and migration of NK cells to tumor sites is a crucial area of research. Factors such as integrins, selectins, and chemokine receptors (e.g., S1P5, CX3CR1, CXCR4, VLA-4, CCL3, CXCR6, CCR5, CCL25-CCR9) play significant roles in regulating NK cell trafficking and recruitment to peripheral tissues, including the TME [ 45 – 47 ]. Interestingly, conventional chemotherapy can paradoxically enhance anti-tumor immunity. It achieves this by inducing immunogenic cell death, which leads to the release of tumor-associated antigens and damage-associated molecular patterns that activate immune responses [ 48 , 49 ]. Chemotherapy can also promote dendritic cell maturation and improve CD8 + T cell activation through efficient antigen presentation [ 48 ]. Furthermore, certain chemotherapeutic agents can enhance NK cell infiltration into tumors by modulating the TME and immune responses, upregulating NK cell-activating ligands on cancer cells, and promoting the release of activating cytokines like IL-2 and IFN-γ [ 48 , 50 ]. This suggests that chemotherapy can prime the TME for subsequent NK cell-based therapies. Personalized therapeutic approaches, guided by the specific characteristics of NK cell subsets (e.g., CD16 + expression or elevated NKG2A + NK cell infiltration within the TME), may involve combination strategies with monoclonal antibodies (e.g., anti-CD20) or co-administration with NKG2A inhibitors (e.g., monalizumab) to optimize therapeutic outcomes [ 45 , 51 ].

Macrophage-based immunotherapies for blood cancers

The dual role of macrophages in the tumor microenvironment: M1 vs. M2 polarization

Macrophages are highly abundant innate immune cells within the tumor microenvironment (TME), present throughout all stages of tumor progression. 3 While macrophages possess inherent tumoricidal capabilities when activated in vitro, they paradoxically adopt a predominantly pro-tumoral phenotype in vivo, particularly within established tumors [ 52 , 53 ]. This pro-tumoral phenotype, often referred to as M2-like polarization, is consistently associated with poor prognosis across many cancer types, including various hematologic malignancies [ 54 , 55 ].

M2-polarized tumor-associated macrophages (TAMs) actively contribute to tumor progression through a multitude of mechanisms. They stimulate angiogenesis, enhance tumor cell invasion, motility, intravasation, and extravasation, and promote persistent tumor growth [ 52 , 56 ]. Critically, these TAMs also induce profound immunosuppression within the TME, actively preventing effective anti-tumor attacks by NK cells and T cells [ 52 , 57 ]. However, classically activated M1 macrophages are recognized for their anti-tumoral functions, exhibiting robust Th1-like inflammatory responses [ 58 , 59 ]. The TME, heavily influenced by signals from tumor cells and various cytokines (e.g., TGF-β, lactic acid, sonic hedgehog (Shh)), causally biases macrophages towards the M2 pro-tumoral phenotype [ 52 , 60 ]. Thus, simply activating macrophages might be insufficient; a sustained anti-tumor effect requires strategies to actively repolarize or prevent M2 polarization. This makes TME modulation a critical co-strategy for any macrophage-based immunotherapy [ 61 ].

Strategies for repolarizing tumor-associated macrophages (TAMs)

Given their remarkable plasticity, macrophages are highly responsive to environmental stimuli, presenting unique opportunities for therapeutic re-differentiation or targeted ablation [ 52 , 62 , 63 ]. A key therapeutic objective in cancer immunotherapy is the repolarization of TAMs from their pro-tumorigenic M2 phenotype to an anti-tumorigenic M1 phenotype [ 64 , 65 ]. Emerging strategies to achieve this include targeting macrophage-derived and cancer cell-derived exosomes, which are known mediators of tumor immune evasion and M2 polarization [ 64 , 66 ]. Bacterial therapy also represents a novel approach, utilizing specific bacterial strains that stimulate M1 polarization (e.g., Listeria monocytogenes ) to induce the repolarization of TAMs [ 64 ]. Furthermore, nanocarriers are being investigated as precise delivery systems for therapeutic agents into the TME, aiming to selectively repolarize M2 macrophages [ 64 , 67 , 68 ].

Adoptive macrophage transfer and its therapeutic potential

Adoptively transferred macrophages, when optimally activated ex vivo, function as a potent cellular cancer therapeutic platform [ 69 ]. These engineered macrophages are capable of eliciting systemic immune responses, infiltrating tumors effectively, and exerting direct anti-tumor effects [ 69 ]. Their unique ability to coordinate multi-armed anti-tumor immune attacks involves the participation of diverse lymphocyte populations, including CD8 + T cells, NK cells, and CD4 + T cells, thereby inducing a “hot” tumor transition [ 70 – 72 ]. Macrophages’ natural function as antigen-presenting cells and their inherent tumor-homing capability make them particularly attractive candidates for adoptive transfer therapies [ 69 ]. Ex vivo activation cocktails, typically comprising interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), polyinosinic: polycytidylic acid, and anti-CD40 antibody, can significantly enhance their therapeutic potency prior to administration [ 70 ].

CD47 blockade and its impact on macrophage-mediated phagocytosis

CD47, a cell surface protein ubiquitously expressed on both healthy and malignant cells, plays a crucial role in immune evasion by interacting with signal regulatory protein alpha (SIRPα) on myeloid cells. This interaction transmits a “don’t eat me” signal, effectively preventing cancer cells from immune detection and phagocytosis by macrophages [ 73 ]. CD47 blockade, a therapeutic strategy that disrupts this inhibitory signal, enables phagocytic immune cells like macrophages to recognize and eliminate cancer cells [ 73 , 74 ]. Preclinical studies have consistently demonstrated that CD47 blockade significantly enhances the phagocytosis of cancer cells by macrophages and promotes broader anti-tumor immune responses [ 73 ].

The CD47-SIRPα axis represents a fundamental immune checkpoint that cancer cells exploit to evade phagocytic clearance. Blocking this interaction directly causes the restoration of macrophage phagocytic activity, implying that CD47 blockade could serve as a potent sensitizer for other immunotherapies or even conventional treatments by removing a key “brake” on innate immune cell function [ 75 ]. However, this interaction also plays a crucial physiological role in protecting normal hematopoietic stem cells (HSCs) and red blood cells (RBCs) from being phagocytosed by macrophages [ 76 ]. This implies a critical challenge: therapies targeting CD47 must carefully navigate potential on-target, off-tumor toxicities, necessitating meticulous dose optimization or the development of more specific targeting strategies to spare healthy cells while effectively eliminating malignant ones [ 77 ].

Emergence of CAR-macrophages (CAR-M) and their distinct mechanisms

Chimeric Antigen Receptor (CAR)-engineered macrophages (CAR-M) represent a promising and innovative approach to enhance cancer recognition and overcome some of the limitations observed with CAR-T cells, particularly in the context of solid tumors [ 64 ]. CAR-M cells offer distinct advantages, including enhanced infiltration and survival capabilities within the challenging TME, and a diverse array of anti-tumor mechanisms [ 64 ]. Beyond direct tumor cell elimination, CAR-M cells are capable of reprogramming macrophages towards an M1 phenotype, thereby contributing to a more immunostimulatory TME [ 64 , 78 ].

First-generation CAR-M constructs typically comprise an extracellular single-chain variable fragment (scFv) for specific tumor antigen recognition (e.g., CD19, HER2) and an intracellular signaling domain (e.g., CD3ζ, FcγR) [ 79 ]. Second-generation CAR-M designs aim to further improve antigen presentation and T cell activation by incorporating additional intracellular cytoplasmic domains [ 79 ]. An anti-HER2 CAR-M (CT-0508) has successfully entered a first-in-human Phase 1 clinical trial for patients with recurrent or metastatic HER-2 overexpressing solid tumors, demonstrating encouraging early results and receiving fast track designation from the FDA [ 79 , 80 ].Despite these advancements, challenges persist, including the limited in vivo expansion and persistence of CAR-M cells, the potential for off-target toxicity due to the expression of targeted tumor-associated antigens on healthy cells, and the possibility of immunogenicity arising from non-self components of the CAR construct or gene-transfer vectors [ 79 , 81 ].

Dendritic cell-based immunotherapies for blood cancers

Dendritic cells as professional antigen-presenting cells and their link to adaptive immunity

Dendritic cells (DCs) are recognized as key sentinels and professional antigen-presenting cells (APCs) that critically bridge the innate and adaptive arms of the immune system [ 82 ]. They are indispensable for initiating and sustaining effective T-cell-mediated anti-tumor immune responses, while also playing a vital role in maintaining immune tolerance [ 82 ]. DCs possess a unique ability to interpret diverse environmental stimuli, efficiently capture, process, and present both self and non-self antigens to T cells, thereby priming highly specific antigen-driven immune responses [ 82 , 83 ].

DCs constitute a heterogeneous population of immune cells, encompassing various subsets such as conventional DCs (cDCs, including cDC1s and cDC2s), plasmacytoid DCs (pDCs), and monocyte-derived DCs (moDCs), each endowed with specialized functions [ 84 ]. For instance, cDC1s are particularly adept at cross-presenting tumor-associated antigens to CD8 + T lymphocytes, a function critical for robust anti-tumor immunity [ 84 ]. Plasmacytoid DCs are prominent producers of type I interferons and can exhibit both anti-tumor and, paradoxically, tumor-promoting roles [ 83 , 84 ]. The pivotal role of DCs in bridging innate and adaptive immunity implies that their proper function is causally necessary for a robust, sustained anti-tumor adaptive immune response. If DCs become dysfunctional, for example, due to suppression within the tumor microenvironment [ 84 ], the entire adaptive immune response against cancer is profoundly compromised. This highlights that DC-based therapies are not merely about activating T cells, but about restoring a fundamental immunological pathway often subverted in cancer, making them critical for the conversion of “cold” tumors into “hot” ones [ 85 ].

Dendritic cell vaccine approaches for hematological malignancies

Dendritic cell (DC)-based vaccination represents an established approach for harnessing a patient’s own immune system to eliminate tumor cells [ 86 ]. The primary objective of DC vaccines is to induce tumor-specific effector T cells capable of reducing tumor mass and, crucially, to establish immunological memory to prevent disease relapse [ 87 ]. DCs are often referred to as “nature’s adjuvants” due to their superior capacity for antigen acquisition, processing, and presentation, coupled with their high expression of co-stimulatory or co-inhibitory molecules that dictate immune activation or anergy [ 86 , 88 ].

In the context of hematological malignancies, DC vaccines have undergone evaluation in numerous preclinical and early clinical trials, yielding promising results that demonstrate their potential to elicit specific cytotoxic immune responses against residual cancer cells [ 89 ]. Various methodologies involve priming autologous DCs ex vivo with tumor-associated antigens (TAAs) and co-stimulatory molecules before re-infusion into the patient [ 89 ].

Strategies to improve dendritic cell antigen presentation and activation

An effective DC vaccine must possess and maintain several critical characteristics: it must efficiently migrate to lymph nodes, exhibit a mature, Th1-polarizing phenotype that is stably expressed after infusion, and present antigen for a sufficient duration to elicit a robust T-cell response capable of eliminating a tumor [ 90 , 91 ]. Strategies aimed at enhancing antigen delivery into DCs are paramount for improving overall vaccination efficacy [ 92 ]. Antigen sources can vary, including peptides (which are fast and simple but often HLA-restricted), tumor lysates, or whole tumor cells [ 90 ]. The use of overlapping peptide libraries that cover entire tumor antigens can overcome issues of HLA restriction and epitope escape, thereby broadening the T-cell repertoire [ 90 ].

Genetic modification, such as through vector-transduced or transfected DCs, can ensure more stable and long-term antigen presentation compared to simply pulsing DCs with peptides [ 90 ]. For effective T-cell activation, DCs require three crucial “signals”: antigen presented as peptide epitopes on MHC molecules; membrane-bound co-stimulatory molecules like CD80 and CD86; and soluble co-stimulatory molecules, particularly the pro-inflammatory cytokine IL-12 [ 90 ].Furthermore, in vivo targeting of DCs offers a promising avenue to simplify vaccine production by generating antigen-specific DCs under more physiological conditions, circumventing the need for ex vivo cell isolation and manipulation [ 90 ] (Fig. 2 ). Fig. 2 Schematic overview of dendritic cell (DC) biology and therapeutic applications. Left panel: DCs as professional antigen-presenting cells capture and process antigens, presenting them to T cells via MHC molecules and delivering co-stimulatory signals, thereby bridging innate and adaptive immunity. Middle panel: DC vaccine approach for hematological malignancies—patient-derived DCs are primed ex vivo with tumor-associated antigens (TAAs) and co-stimulatory molecules, then re-infused to stimulate tumor-specific T cell responses. Right panel: Strategies to enhance DC antigen presentation and activation—antigen loading, upregulation of co-stimulatory molecules (CD80, CD86) and cytokines (IL-12), and in vivo targeting to optimize migration, T cell activation, and durable anti-tumor immunity

Limitations of current DC vaccine strategies and the immunosuppressive tumor microenvironment

Despite their considerable potential, DC-based vaccines have encountered several barriers that have limited their effectiveness in clinical trials [ 89 ]. Major limitations include the variable activation state of the DCs, the inherent challenge of ensuring stable maturation and efficient migration to lymph nodes in vivo, and the difficulty in directly assessing antigen-specific T-cell sensitization post-vaccination [ 87 , 89 ].

The immunosuppressive tumor microenvironment (TME) represents a significant impediment, profoundly hindering DC function by altering their phenotype and promoting dysfunction or tolerogenicity [ 84 ]. This is particularly evident in “cold” tumors, where immunostimulatory cells are downregulated [ 93 , 94 ]. The TME’s ability to induce DC dysfunction and tolerogenicity directly causes a failure to launch effective anti-tumor T-cell responses, even in the presence of tumor antigens. These results indicates that DC vaccine efficacy is intrinsically linked to the TME’s immune status. Therefore, successful DC-based therapies, especially in advanced or “cold” tumors, will likely require pre-conditioning or concomitant strategies to neutralize TME-mediated immunosuppression and ensure DCs mature into an immunostimulatory phenotype rather than a tolerogenic one. DCs can, in certain contexts, inadvertently induce immune tolerance (e.g., through T-cell deletion or the expansion of regulatory T cells) rather than potent anti-tumor activity, which can severely limit vaccine success [ 89 ]. Tumor progression and existing immune dysfunction in advanced disease stages may also render DC-based vaccines more efficacious when applied in earlier disease stages [ 89 , 95 ]. Traditional DC vaccines often struggle with limited therapeutic efficacies and immune-related side effects, underscoring the pressing need for new generations of DC vaccine platforms [ 93 ].

Next-Generation DC vaccine platforms

To address the limitations of current DC vaccine strategies, new generations of DC vaccines are being developed. These include biomaterial-based vaccines, approaches that induce immunogenic cell death, mRNA-pulsed DCs, and DC small extracellular vesicle (sEV)-based vaccines, as well as tumor sEV-based DC vaccines [ 93 ]. These advanced platforms aim to target a broader spectrum of intracellular antigens, effectively prime naive tumor-reactive CD8 + T cells (a capability that distinguishes them from immune checkpoint blockades), and generate long-lived memory CD8 + T cells to prevent tumor relapse [ 93 , 96 ].

Synergistic approaches and overcoming the immunosuppressive tumor microenvironment

Cross-talk between innate immune cells and adaptive immunity

Innate immune cells are not merely direct effectors; they play a crucial role in shaping the cytokine and chemokine milieu of the tumor microenvironment (TME), thereby significantly influencing dendritic cell (DC) activation and the differentiation of effector T cells [ 22 ]. Productive cross-talk between innate cells and T cells can substantially bolster T cell function and proliferation, as exemplified by neutrophil-T cell interactions [ 22 , 97 ]. Furthermore, intratumoral innate leukocytes can engage in beneficial cross-talk with other innate cells; for instance, activated eosinophils have been shown to promote the M1 polarization of intratumoral macrophages, shifting them towards an anti-tumor phenotype [ 22 ]. A particularly important interaction is the NK-DC cross-talk, which, often mediated by FcγRIIIa on NK cells, can enhance DC maturation and the subsequent priming of anti-tumor CD8 + T cells [ 22 , 98 ]. The multifaceted roles of innate cells, encompassing direct cytotoxicity, TME modulation, and bridging to adaptive immunity, indicate that combining therapies targeting different innate cell functions could lead to synergistic effects. This suggests a causal chain where direct killing, coupled with TME modulation and adaptive priming, results in an enhanced and more durable anti-tumor response. This also implies that innate cell therapies are not just alternatives but essential partners for adaptive immunotherapies [ 99 ].

Combination strategies involving NK cells, macrophages, and DCs with conventional therapies or checkpoint inhibitors

Novel therapeutic strategies are increasingly focusing on targeting innate immunity to enhance anti-tumor responses. These include the therapeutic stimulation of pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), and the DNA sensing cGAS/STING pathway [ 22 ]. Therapeutic monoclonal antibodies can effectively recruit innate effector cells, including NK cells, neutrophils, and other myeloid cells, to kill tumor cells through antibody-dependent cellular cytotoxicity (ADCC) [ 22 ]. Immune checkpoint inhibitors (e.g., anti-CTLA-4, anti-GITR, anti-OX40) may exert their anti-tumor activity by selectively depleting regulatory T cells (Tregs) via ADCC and/or antibody-dependent cellular phagocytosis (ADCP), mediated by FcγR-expressing macrophages and other innate immune effectors [ 22 , 23 ].

Conventional chemotherapy, while primarily cytotoxic, can paradoxically enhance anti-tumor immunity by inducing immunogenic cell death, which releases tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs) [ 48 , 100 ]. It also promotes DC maturation, improves CD8 + T cell activation, and increases NK cell infiltration and activity [ 48 ]. However, chemotherapy can also promote pro-tumor inflammation and M2 macrophage polarization within the TME [ 48 , 101 ]. This presents a significant paradox: chemotherapy, while beneficial for some immune aspects, simultaneously causes detrimental effects like pro-tumor inflammation and M2 polarization. This contradiction implies that combining chemotherapy with innate immune cell therapies requires careful consideration and strategic timing. It suggests that therapies aimed at repolarizing M2 macrophages or dampening TME inflammation might be crucial adjuncts to chemotherapy, transforming its dual nature into a more consistently pro-immunogenic effect [ 102 ] (Fig. 3 ). Fig. 3 Schematic representation of novel therapeutic strategies aimed at enhancing anti-tumor immunity by engaging innate immune mechanisms. PRR stimulation via TLRs and the cGAS/STING pathway promotes innate immune activation against tumor cells. Therapeutic antibodies recruit NK cells and other innate effectors to mediate ADCC. Immune checkpoint inhibitors (anti-CTLA-4, anti-GITR, anti-OX40) can deplete Tregs through ADCC/ADCP, enhancing anti-tumor immunity. Chemotherapy induces immunogenic cell death, leading to DC maturation, CD8⁺ T cell activation, and NK cell infiltration, while also potentially causing pro-tumor inflammation and M2 macrophage polarization, highlighting the need for combination approaches to counteract these adverse effects

Targeting the tumor microenvironment to enhance innate immune cell function

The tumor microenvironment (TME) is a critical determinant of therapeutic efficacy, often characterized by profound immunosuppression and the downregulation of immunostimulatory cells [ 93 ]. Strategies aimed at overcoming TME limitations are therefore essential for enhancing both the numbers and functions of effector T cells and antigen-presenting cells (APCs) [ 93 , 103 ]. Repolarizing tumor-associated macrophages (TAMs) from an M2 (pro-tumorigenic) to an M1 (anti-tumorigenic) phenotype is a key TME-modulating strategy [ 58 ]. CD47 blockade directly disrupts a pivotal TME-mediated immune evasion mechanism, thereby unleashing phagocytic cells [ 73 , 104 ]. The overarching goal of these strategies is to convert immunologically “cold” tumors, which are unresponsive to many immunotherapies, into “hot” tumors, characterized by robust immune cell infiltration and activity [ 70 , 105 ].

To provide a comprehensive overview of the current translational landscape and the challenges being addressed, the following tables (Tables 1 and 2 ) summarize key clinical trials and the strategies employed to enhance innate immune cell therapies. Table 1 Clinical trials of innate immune cell therapies in blood cancers Cell Type Therapy Type Target Malignancy Phase of Trial Key Findings (Efficacy/Safety Highlights) Relevant Citations NK Cell Adoptive Transfer Acute Myeloid Leukemia (AML) Phase 1 Feasible, safe (“off-the-shelf” aNK), no dose-limiting toxicities or grade 3–4 toxicities, transient activity in some patients. [ 31 ] NK Cell Adoptive Transfer Acute Myeloid Leukemia (AML) Various Varying efficacy (transient activity to sustained remission), favorable safety (minimal CRS/GVHD), limited persistence. [ 27 ] NK Cell CAR-NK Cells B cell malignancies Early Clinical Promising efficacy, response rates comparable to CAR-T cells, lower rates of severe adverse effects (CRS). [ 30 ] Macrophage CAR-M (CT-0508) HER-2 overexpressing solid tumors (not blood cancer, but relevant for CAR-M development) Phase 1 Encouraging results, fast track designation. [ 79 ] Dendritic Cell DC Vaccine Hematological Malignancies Preclinical/Early Clinical Promising results, potential for specific cytotoxic immune response against residual cancer cells. [ 89 ] Table 2 Challenges and strategies to enhance innate immune cell therapies Challenge Relevant Cell Type(s) Proposed Strategy Mechanism of Action Relevant Citations Limited Cell Persistence NK, Macrophage, DC Cytokine treatment (IL-15, IL-2), Feeder cell lines, Genetic engineering (CAR-NK, CAR-M) Promotes expansion, survival, and sustained anti-tumor function. [ 45 Poor Homing/Infiltration NK, Macrophage Genetic engineering (e.g., chemokine receptor expression), Chemotherapy pre-treatment Enhances migration to tumor sites, modulates TME for better infiltration. [ 45 ] Immunosuppressive TME NK, Macrophage, DC TME modulation (e.g., repolarizing TAMs), CD47 blockade, Combination with checkpoint inhibitors Neutralizes suppressive factors, enhances phagocytosis, re-educates immune cells. [ 41 ] On-target/Off-tumor Toxicity CAR-NK, CAR-M, CD47 blockade Refined CAR design, Specific antigen selection, Careful dose optimization Minimizes recognition of healthy cells, balances efficacy with safety. [ 38 ] Functional Exhaustion NK, Macrophage, DC TME modulation, Combination therapies, Advanced engineering Counters TME-induced suppression, restores cytotoxic and proliferative capacity. [ 45 ] Antigen Escape (for CAR-based) CAR-NK, CAR-M Retained CAR-independent cytotoxicity (NK), Multi-antigen targeting Maintains anti-tumor activity even if CAR target is lost. [ 30 ]

Conclusion and future perspectives

Recent advances in immunotherapy have expanded the focus beyond adaptive immune cells to include innate immune effectors as clinically relevant therapeutic agents in hematological malignancies. NK cells, macrophages, and dendritic cells contribute to anti-tumor immunity through distinct yet interconnected mechanisms, including direct cytotoxicity, modulation of the tumor microenvironment, and initiation of adaptive immune responses. Harnessing these properties has led to the development of adoptive NK cell therapies, CAR-engineered innate immune cells, and dendritic cell–based vaccines.

Despite these remarkable advancements, the path to widespread clinical success is fraught with persistent challenges. Limited in vivo persistence and suboptimal homing to tumor sites remain critical hurdles for all three cell types. The immunosuppressive tumor microenvironment, characterized by metabolic barriers and suppressive cellular components, profoundly hinders the function of these innate immune effectors, often leading to their exhaustion or tolerogenic reprogramming. Furthermore, the potential for on-target, off-tumor toxicities, as exemplified by CD47 blockade’s impact on healthy hematopoietic cells, necessitates meticulous therapeutic design.

The future of innate immunity-based immunotherapies for blood cancers lies in a multi-pronged, synergistic approach. Continued research must focus on:

Enhanced Cell Persistence and Homing : Developing sophisticated strategies to overcome the limitations of in vivo longevity and targeted tumor infiltration for NK cells, macrophages, and DCs. This includes optimizing cell expansion protocols and engineering cells with improved trafficking capabilities. Precision TME Modulation : Designing therapies that specifically neutralize immunosuppressive factors and cells within the TME while simultaneously promoting pro-immunogenic signals. This involves understanding the intricate interplay of cytokines, metabolites, and cellular components that dictate the TME’s immune status. Multi-modal and Personalized Approaches : Exploring rational combinations of innate cell therapies with conventional treatments (e.g., chemotherapy), immune checkpoint inhibitors, or other immunotherapies. Such approaches must be meticulously tailored to individual patient and tumor characteristics, moving towards precision medicine. Advanced Engineering : Leveraging cutting-edge technologies like CRISPR/Cas9 gene editing, synthetic biology, and nanotechnology to create “smart” immune cells. These next-generation cells could possess enhanced anti-tumor functions, inherent resistance to TME-induced suppression, and improved safety profiles, potentially even secreting TME-modulating factors. Biomarker Discovery : Identifying robust predictive biomarkers for patient response to innate immune cell therapies is paramount. Such biomarkers will guide treatment selection, enable early identification of non-responders, and optimize therapeutic outcomes. Addressing Relapse Mechanisms : A deeper understanding of the mechanisms underlying tumor relapse post-therapy, including antigen escape and the re-education of the TME, is crucial for designing durable therapeutic strategies.

The ultimate goal is to translate these scientific breakthroughs into safe, durable, and widely accessible therapeutic options that offer sustained remission and improved quality of life for patients battling hematological malignancies. The concerted efforts across fundamental biology, translational research, and clinical trials will be indispensable in realizing the full therapeutic potential of harnessing innate immunity.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author contributions

Ghaleb Oriquat, Waleed K. Abdulsahib, Sajida Hussein Ismael, R. Roopashree, Pradeepta Sekhar Patro, Jayshree Nellore, Gunjan Mukherjee, Ashish Singh Chauhan, Saodat Musayeva contributed to the conception, design, and drafting of the manuscript.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Consent for publication

Not applicable.

Ethical approval and consent to participate

Not applicable.

Clinical trial number

Not applicable.

Competing interests

The authors declare no competing interests.

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