1 Introduction

With only 12% of patients living for 5 years following diagnosis, pancreatic ductal adenocarcinoma (PDAC), often commonly referred to as PC, has an extremely poor prognosis when compared to other cancers [1]. PDAC accounts for over 90% of PC occurrences [2]. In 2018, the global age-standardized incidence rate of PC was 4.8 per 100,000 [3]. While the occurrence of PC is increasing in most regions worldwide, high-income countries have the highest levels of incidence and mortality [4]. PC is associated with a significant degree of resistance to systemic therapy strategies [5]. The close proximity of numerous organs-at-risk and wide spatial variations make radiation therapy for PC very difficult [6]. Additionally, the PC is extremely resistant to current immunotherapies due to its immunosuppressive TME, which restricts the effectiveness of T cell infiltration [7]. Given its crucial involvement in both the cancer progression and treatment resistance, the TME has been recognized as a viable target for therapeutic intervention in a variety of malignancies [8]. TME consists of various cell types, including immune cells such as B and T lymphocytes, TAMs, myeloid-derived suppressor cells (MDSCs), as well as cancer-associated fibroblasts and pericytes [9].

PDAC is characterized by the desmoplastic stroma, an immunosuppressive microenvironment that forms a barrier to protect tumor cells from immunologic elimination and prevents chemotherapeutic penetration [10]. The stroma, mainly composed of proliferating fibroblasts, deposits collagen, fibronectin, and other extracellular matrix components. It also produces cytokines and chemokines to crosstalk with lesion cells and immune cells [11, 12].

PC suppresses cytotoxic T lymphocytes (CTLs) through immunosuppressive interaction with stromal cells in the TME. Combining immunotherapeutic approaches is suggested for infiltrating active T lymphocytes or rescuing exhausted CTLs. Maintaining activated CTLs in the TME is crucial for tumor immunotherapy [13]. The TME is characterized by hypoxia, acidity, increased permeability, and a high number of growth factors and hydrolases and numerous growth factors, leading to insensitivity to apoptosis, resistance to growth inhibition and immune escape [14]. The immunosuppressive microenvironment in PC is essential for malignant tumor development and is an obstacle for immunotherapy [15]. The cancer lacks the expression of immunogenic antigens and their major histocompatibility antigens (MHC) class I molecules, leading to decreased activity of effector T cells. In addition, the functions of effector T cells such as natural killer (NK) cells, dendritic cells (DCs), and macrophages are greatly reduced, while suppressive immune cells such regulatory T-cells, MDSCs, and M2-TAMs accumulate in the TME [16, 17]. One of the main agents in this regard that promotes carcinogenesis, tumor growth, and progression, as well as treatment resistance, are macrophages [18]. Pre-clinical PDAC mouse models have clearly shown the significance of these cells in promoting angiogenesis, matrix remodeling, immunosuppression, tumor cell invasion, and treatment resistance [19, 20].

Understanding the function of macrophages within the PC TME is essential for developing innovative approaches for treatment and management of this diseases. In this review, we aimed to outline the role of macrophages in PC TME and investigate their potential as therapeutic targets.

2 Macrophages: the double agents

As crucial elements of the immune system, macrophages are essential for the modulation of immunological responses, regulation of inflammatory processes, tissue remodeling, and surveillance of immune activities [21]. These cells participate in both the innate and adaptive immune responses, among their many other roles in the immune system. Macrophages become activated in response to cytokines and other environmental stimuli, such as microbial compounds. M1 and M2 are the two different subtypes of activated macrophages (Fig. 1). The M1 type represents the phenotype that is traditionally active, whereas the M2 type represents the phenotype that is alternatively activated [22]. The M1 macrophages play a crucial role in immunity against intracellular infections and malignancies. Through the creation of tumoricidal substances like interleukin (IL)-12, IL-6, and tumor necrosis factor-α (TNF-α), they eliminate harmful tissue reactions [23]. Conversely, M2 macrophages suppress the immune system and are often activated by IL-4 and IL-13. They release cytokines including transforming growth factor-β (TGF-β) and IL-10 which trigger a T helper 2 (Th2) immune response [24]. Larger tumors, early hepatic recurrence, local recurrence, and a shorter survival time for PC patients are all associated with higher concentrations of M2 macrophages [25].

Fig. 1
figure 1

Subtypes of activated macrophages and their receptors, signaling pathways, related cytokines, and functions

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Macrophages have notable plasticity, enabling them to effectively react to diverse stimuli and experience significant physiological alterations in reaction to different stimuli from the environment [26]. The plasticity that macrophages demonstrate enables them to transition between several activation states, among them are the anti-inflammatory M2 phenotype and the pro-inflammatory M1 phenotype, in reaction to distinct signals originating from their surrounding environment [27].

The signals encompass a range of factors including cytokines, microbial compounds, and various environmental stimuli [28]. Polarization is notably impacted by diverse signaling pathways.

Notch signaling system assumes crucial functions in the determination of macrophage polarization, namely in distinguishing between M1 and M2 phenotypes. These paths include PI3K-Akt, WNT, MAPK, NF-κB, STAT, IRF, JAK, and hedgehog signaling pathway [29, 30].

2.1 Angiogenesis

An angiogenic switch allows cancer cells to hijack blood supplies to enhance their progress and persist. In this key process which was recruited and reprogrammed by tumor cells, the role of monocyte-derived macrophages, as a major source of angiogenic factors, is undeniable [31]. In TME, TAMs reprogrammed by tumor cells mediated by exudation of some factors such as CC chemokine ligand 2, TGF-β, and VEGF-A which can facilitate tumor angiogenesis. It was proven that these factors play the main role in the switching of the macrophage phenotype from the M1 into the M2 phenotype, as the M2 phenotype has a high capacity to enhance tumor angiogenesis [32, 33]. Macrophages regulate the presence of VEGF-A in tumors by altering its availability through the action of matrix metalloproteinases (MMPs) [34]. Moreover, an increase in VEGF in contrast to a decrease in colony-stimulating factor 1 (CSF-1) activity results in the recruitment of macrophages and the continuance of vascularization and angiogenesis, all of which work toward an accelerated advancement of cancer [35]. Esposito et al. [36] reported the expression of proangiogenic and prolymphangiogenic molecules including VEGF-A, VEGF-C, and bFGF in patients with PC. They found significantly more mast cells and macrophages in these patients than in normal individuals, which had a direct correlation with intratumorous microvessel density. Lewis et al. [37] reported that TAMs upregulate VEGF expression in hypoxic and avascular regions of the beast tumor, as macrophages accumulation was found in higher numbers in poorly vascularized than highly vascularized areas. VEGF seems to exert a chemotactic action on macrophages to enhance their migration into avascular tumor regions. Furthermore, compared to VEGF-negative locations, TAMs are more common in VEGF-positive, weakly vascularized regions, indicating a potential function for VEGF in macrophage chemoattraction. In addition, in hypoxic conditions, macrophages upregulate MMPs and hypoxia-inducible factor (HIF)-regulated genes, which enable cancer cells to survive in hostile environments and result in the revascularization of tumor ischemia sites [38].

2.2 Immunosuppression

MDSCs are a kind of immune cell that has gained significant attention in recent years due to its immunosuppressive properties. They are closely linked to macrophages. MDSCs are a diverse collection of cells with a myeloid origin that gather in pathological circumstances, such as cancer. From a morphological perspective, these populations are composed of immature myeloid cells, granulocytes, and monocytes. They may be distinguished by their capacity to prevent responses from cytotoxic T cells. The granulocyte marker Gr1 and the myeloid cell marker CD11b are co-expressed by MDSCs in mice. Given the traditional definition of neutrophils, the presence of these markers suggests that MDSCs are not mononuclear phagocytes. The examination of cell surface markers has been further supported by gene expression analysis, which demonstrates significant differences between MDSCs and TAMs [39, 40].

As mentioned, monocytes in tumors change into polarized or M2 macrophages in response to exposure to tumor-derived anti-inflammatory chemicals. The antigen presentation capacity of these macrophages is deficient, and they secrete substances that suppress the activity and proliferation of T-cells [33]. They possess superior adaptations for scavenging detritus, facilitating angiogenesis, and healing and rebuilding injured or damaged tissues. This is in stark contrast to the profile of traditionally activated type I, or M1 macrophages, are immune effector cells with a high degree of effectiveness capable of eliminating pathogens and tumor cells, presenting antigens, and producing significant amounts of immunostimulatory cytokines [41]. Comparable with regard to their molecular and functional profile, TAMs are distinguished by decreased TNF levels, increased constitutive expression of IL-6 and IL-1, and decreased expression of differentiation-associated macrophage markers such as carboxy peptidase M and CD51 [42, 43]. TAMs also release chemokines (e.g. C–C Motif chemokine ligand-7 (CCL7) and CCL2) and anti-inflammatory/immunosuppressive cytokines (e.g. TGF-β, PGE2), which encourage T-cell exhaustion and create a self-replicating tumor-permissive environment [29, 44]. Furthermore, NK cell proliferation is hindered by IL-10 produced from macrophages, and NK cell cytolytic activity is inhibited by TGF-β signaling in TAMs in a contact-dependent way [45, 46].

Additionally, TAMs have the ability to increase the production of ligands that attach to inhibitory receptors on the surface of T cells to prevent T-cell activation, proliferation, and effector activities [47]. These consist of CD80/CD86 and PDL1/PDL2, which attach to the surface of CD8 T-cells in response to CTLA4 and PD1, respectively. Dectin1 is one of the other ligands; in mouse and human PDAC, macrophages express it at a high level. Dectin1 binds to Galectin-9 on the surface of cancerous and invading immune cells, suppressing adaptive immunological responses and training tolerogenic macrophages [48].

2.3 Metastasis

Macrophages have the capacity to create an autocrine loop that stimulates cancer cell migration, which in turn encourages invasion and eventual metastasis from the initial tumor location. CSF-1, which is produced by cancer cells, stimulates macrophages to create EGF. This autocrine signaling process leads to comigration of cancer cells and macrophages toward tumor blood vessels, where VEGF-A derived from macrophages facilitate the infiltration of cancer cells into the blood vessels [49, 50]. Tissue macrophage hemostasis is aided by a unique cytokine known as IL-34. The colony-stimulating factor 1 receptor (CSF-1R) can bind to it and initiate a signaling pathway that leads to macrophage proliferation, survival, and differentiation [51]. It has been demonstrated that this function can be performed by it as an alternative ligand for CSF-1R. One important regulator of macrophage populations is CSF-1 which also functions as a chemotactic factor for macrophages [52]. Myeloid progenitor cells can differentiate into monocytes and macrophages with the help of CSF-1, which also regulates the growth, survival, and migration of macrophages [53].

Macrophages facilitate the movement of stalled disseminated tumor cells (DTCs) from capillary networks to the secondary location. Dysplastic tumor cells secrete CCL2, which attracts bloodstream-derived inflammatory monocytes to the metastatic location [54]. In this context, inflammatory monocytes release VEGF-A to facilitate the extravasation of DTCs by enhancing vascular permeability. Furthermore, CCL2 stimulates the production of CCL3 by metastasis-associated macrophages (MAMs), which in turn enhances the ability of MAMs to remain at the site of metastasis. This enhances the direct interaction between macrophages and cancer cells by means of VCAM1-α4 integrin mediated signaling, hence facilitating the retention of cancer cells at the metastatic location [55]. Moreover, DTCs can draw platelets and start the coagulation cascade by the production of tissue factor, which activates thrombin and deposits fibrin, finally causing blood clots to form. Macrophages are attracted to the clots that form around cancer cells. They support the survival of these cancer cells by a process that does not involve NK cells [56]. This could be explained by the direct relationship that exists between MAMs and DTCs, since studies have shown that macrophages enhance the survival of DTCs by establishing physical contact between the cells. In this context, pro-survival signaling in cancer cells is activated via the PI3K/Akt signaling pathway by DTCs expressing higher levels of VCAM-1 interacting with α4-integrins on MAMs [57].

MAMs are essential in promoting the spread of PC cells by facilitating the development of a metastatic environment in the liver. Upon the entrance of DTCs, there is an accumulation of monocytes with inflammatory characteristics in the liver, which thereafter differentiate into monocyte-derived macrophages. Local hematopoietic stem and progenitor cells are stimulated to become αSMA+ myofibroblasts by MAMs through the release of granulin. These activated myofibroblasts secrete periostin, an extracellular matrix substance, which augments the colony forming capabilities of PC cells. In the bone marrow region, the absence of granulin eliminates the accumulation of periostin and extracellular matrix in the metastatic growths, leading to decreased proliferation of cancer cells that have already spread to other body regions [58].

2.4 Matrix remodeling

Recent evidence suggests that macrophages can influence the behavior of cancer stem cells (CSCs) and/or tumor starting cells. TAMs have been demonstrated to augment the properties of CSCs in lung and colon cancer, such as boosting their tumorigenicity and resistance to chemotherapy [48]. The milk-fat globule-epidermal growth factor-8 (MFG-E8) produced from TAMs was found to be an essential CSCs activity regulator. This factor triggers the activation of the sonic hedgehog and STAT3 pathways in CSCs. Suppression of the recruitment of macrophages to the PC tumor location, leads to a reduction in PC cells that express high amounts of the CSCs marker aldehyde dehydrogenase. It is noteworthy that in this paradigm, the tumor-initiating characteristics of murine PC cell lines were intensified by conditioned media from macrophages educated by tumors [59].

2.5 Resistance to chemotherapy

In PC cells, macrophages promote the synthesis of cytidine deaminase, the primary enzyme that is responsible for metabolizing the chemotherapeutic agent gemcitabine. Chemotherapy increases the tumor cells' chance of survival when orthotopically implanted pancreatic tumors are treated. This effect can be mitigated by reducing the number of macrophages or inhibiting CCR2+ inflammatory monocytes [60]. Insulin-like growth factor1 (IGF-1) and IGF-2 are another way that TAMs encourage chemoresistance in PC. In an orthotopic PC model, gemcitabine with antibody-mediated neutralization of IGF enhances the response to chemotherapy, reducing tumor growth and increasing cancer cell death [61]. Cathepsin expression in macrophages can also be directly induced by chemotherapeutic agents. The amount of cathepsins produced by macrophages could be adequate to prevent tumor cells from dying, and blocking cathepsins made cancer cells more susceptible to various chemotherapy agents [62].

3 Therapeutic strategies targeting macrophages

Recently, there has been a focus on developing various strategies to counteract detrimental impacts of TAMs, considering their role in promoting tumor growth.

3.1 Depletion of TAMs

Reducing the total number of TAMs within a tumor can be accomplished by either compromising their survival or eliminating preexisting TAMs. Due to the reliance of macrophages on CSF-1R signaling, the primary method for reducing TAMs involves specifically targeting the CSF-1R. CSF-1R is a type III protein kinase receptor that interacts with two ligands, CSF-1 and IL-34. When the receptor binds to its ligands, it triggers the formation of CSF-1R homodimers and activates signaling pathways that are essential for macrophage survival [63]. Blocking CSF-R1 leads to decreased number of TAMs through the inhibition of monocyte differentiation and reduced survival of existing TAMs [64]. Notably, there is ongoing focus on alternative strategies to reduce TAMs directly. These strategies include the use of Trabectedin, which activates caspase 8 through TNF-related apoptosis-inducing ligand (TRAIL), causing monocytes and macrophages within the tumor to undergo apoptosis [65, 66]. The engagement of CSF-1R was validated by a rise in CSF-1 levels and a decrease in CD14lowCD16high monocytes in peripheral blood mononuclear cells [67]. It is important to mention that while these strategies have been explored, their application in reducing TAMs survival has not been thoroughly studied in relation to PC. Ongoing investigations are assessing the effectiveness of different antibodies and receptor antagonists that specifically target CSF-1R to compromise the survival of TAMs. These studies are being conducted in diverse preclinical studies and clinical trials, examining the use of CSF-1R inhibitors as standalone treatments or in combination with other therapies including immunotherapies. Several small molecule inhibitors are employed in the treatment of PC. PLX3397, also known as Pexidartinib, is a receptor tyrosine kinase inhibitor (TKI) that targets multiple receptors including CSF-1R, KIT, and FLT3. However, it is more accurately described as a conformation-specific inhibitor rather than a traditional TKI for CSF-1R, which specifically binds to the autoinhibited state of CSF-1R and directly contacts with the juxtamembrane region [68, 69]. In 2019, the FDA approved its use for treating symptomatic tenosynovial giant cell tumors [70]. To evaluate the safety and efficacy of pexidartinib in combination with durvalumab (an anti-PD-L1 antibody) for patients with advanced colorectal cancer (CRC) and PDAC, a phase I clinical trial was carried out [71]. The objective of the study was to improve PD-L1 blockade responses by the removal of CSF-1-dependent suppressive TAMs. 15% of patients had stable disease, 2% of patients had a partial response, and there were no unexpected toxicities noted BLZ945 is a selective, orally administered investigational inhibitor of CSF-1R tyrosine kinase that can penetrate the brain. In various animal models, including those with intracranial glioblastoma multiforme (GBM), the blockade of CSF-1R by BLZ945 has shown potential in reducing the TAMs’ recruitment to the TME, inhibiting tumor growth, and overcoming resistance to PD-1 inhibitors [64, 69]. Patients with tumors linked to TAMs upregulation, including as GBM (n = 24), PC (n = 19), CRC (n = 10), as well as other types including breast cancer, mesothelioma, and soft tissue sarcoma., were included in a phase I trial to assess the efficacy of BLZ945, both as a monotherapy and in combination with spartalizumab (also called PDR001, an anti-PD-1 antibody). The administration of BLZ945 with or without spartalizumab showed an acceptable safety and efficacy profile [72, 73]. Anti-CSF-R1 antibodies for PC have also garnered attention from researchers. The anti-tumor effectiveness and safety of cyclophosphamide, pembrolizumab (an antibody that inhibits negative signals to T cells), GVAX (a PC vaccination), and IMC-CS4 (also known as LY3022855) in combination are being evaluated in an early phase I clinical trial [74]. The results of this investigation have not yet been published. AMG820 is a fully human monoclonal antibody (mAb) targeting CSF-1R. It is currently under investigation and functions by blocking the ligands CSF-R1 and IL-34 from attaching to the receptor, which prevents the ligand-induced activation of the receptor [69]. A Phase 1b/2 clinical trial is being conducted at multiple centers to evaluate the efficacy of combining AMG820 with pembrolizumab in individuals diagnosed with specific advanced solid tumors including PC. According to Razak et al., a satisfactory safety profile was shown by the combination of 1100 mg AMG820 with 200 mg pembrolizumab at the recommended dose. Nevertheless, in the particular patient populations examined, the demonstrated anticancer activity did not meet the requirements for additional assessment of this combination [75, 76]. BMS-986227 is another antibody that had been studied in a clinical trial and showed pharmacodynamic activity for anti-PD-1/PD-L1–resistant tumors including PC. Additionally, Clodronate has been investigated for its ability to decrease macrophage tumor infiltration [77, 78]. In a recent study, targeting proliferating F4/80+ macrophages enhanced the antitumor response mediated by cytotoxic CD8+ T-cell. Depletion of macrophages using clodronate liposomes decreased proliferating macrophages in PDAC mouse models and increased the proximity of CD8+ T cells to tumor cells. This in turn, led to an increase in IFN-γ+ CD8+ T cells infiltration, promoting an antitumor effect. These findings highlight the potential of targeting proliferating TAMs to enhance CD8+ T-cell infiltration and improve antitumor immune responses in PDAC [79] (Table 1).

Table 1 List of clinical trials targeting TAMs
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3.2 Reprogramming TAMs to promote anti-tumor activity

Reprogramming strategies for TAMs can be divided into two categories. The first category comprises strategies that aim to convert TAMs from a pro-tumoral phenotype to an anti-tumoral one. These strategies focus on targeting either the signaling pathways responsible for macrophage polarization or specific targets/markers expressed by TAMs. The second group, referred to as function-based reprogramming of TAMs, involves therapeutic strategies that specifically target the functions of TAMs, such as immunosuppression and phagocytosis. Furthermore, there are strategies aimed at engineering macrophages to enhance their anti-tumoral properties [80]. While some specific strategies have not been utilized for PC, a brief explanation is given for each method.

3.3 Phenotype reprogramming of TAMs

3.3.1 Reprogramming macrophage phenotype through polarization signaling pathways

PI3K encompasses multiple subclasses, with class 1B PI3Kγ primarily found in hematopoietic cells. Inhibiting this target through genetic and pharmacological agents means results in an increase in the expression of major histocompatibility complex class II (MHC II) molecules, along with elevated IL-12 levels and reduced secretion of IL-10. Consequently, PI3Kγ inhibition in TAMs promotes the recruitment of cells linked to adaptive immunity against tumors and inhibits tumor growth [81, 82]. Histone deacetylase inhibitors (HDACs) are vital in the elimination of acetyl groups from histones in order to epigenetically regulate the gene expression. This may result in a pro-inflammatory phenotype by altering the expression of CCL1 and CCL2 in monocytes. The research conducted by Guerriero et al., demonstrated that inhibitors targeting class IIa HDACs have the ability to reprogram TAMs into anti-tumoral macrophages. In preclinical cancer models, this reprogramming has been demonstrated to improve the effectiveness of immunotherapy and chemotherapy [83, 84]. Toll-like receptors (TLRs) are pattern recognition receptors of the innate immune system and are essentials in activating the innate immune response. TLRs have diverse functions in macrophage activation. They control cytokine production, promote cell survival, participate in the identification of invading pathogens and self and non-self antigens [85]. Numerous anti-TLRs therapeutics have been developed with the aim of repolarizing macrophages from an M2-like to an M1-like activation state [86], thereby enhancing the response of immune system to cancerous cells. The elevation of SNAIL and vimentin in PC cells and the considerable decline of the E-cadherin levels were achieved with the use of TLR4 siRNA and neutralizing antibodies against TLR4 and IL-10, expressed on M2-polarized TAMs [87]. By affecting TAMs polarization, histidine-rich glycoprotein (HRG), an antiangiogenic and immunomodulatory substance generated by the host, has been demonstrated to augment anti-tumor immune responses and promote vascular normalization. Specifically, it shifts TAMs from the M2 phenotype associated with tumor promotion to the tumor-inhibiting M1 phenotype [88]. HRG interacts with various molecules involved in tumorigenesis, including Fcγ receptors (FcγR), thrombospondins (TSPs), heparin. FcγR, expressed in macrophages, has been implicated in promoting the M2 macrophages [89]. However, it is important to note that FcγR can also activate macrophage cytotoxicity in response to Trastuzumab [90, 91].

TMP195 is a specific inhibitor of class IIa HDACs. By targeting these HDACs, TMP195 can alter the epigenomic profile of monocytes and macrophages. Ivaltinostat, Romidepsin, and Vorinostat are inhibitors of class IIa HDACs that several clinical trials have been conducted to investigate their effectiveness on PC. TLR3 agonists such as Poly- ICLC, Rintatolimod, and BO-112, TLR7 agonists such as SHR2150, TransCon, BDC-1001, and TLR9 agonists such as CMP-001 have been evaluated in several clinical trials. Resiquimod (R848) is an immunostimulatory drug that targets TLR 7/8. Both soluble R848 and R848 in nanoparticle formulation have demonstrated effectiveness in various preclinical tumor models. These effects include enhancing survival in a murine pancreatic model [92], transforming M2 macrophages into M1 phenotype, boosting cellular phagocytosis dependent on Ab [93], reorganizing the TME’s myeloid compartment to promote tumor regression [94], and enhancing the efficacy of chemotherapy [95]. Zoledronic acid (ZA) is another therapeutic that aims to reduce the number of TAMs and alter their polarization status [78, 96]. In the context of mesothelioma, ZA was found to reduce the M2 macrophage markers’ expression, including Arg-1, CD206, and TGF-β. Additionally, ZA prevented monocytes from differentiation into macrophages [97, 98]. FGD5-AS1 is a long non-coding RNA (lncRNA), is linked to high IL-6 expression and poor prognosis in PC patients. Through the STAT3/NF-κB pathway, exosomal FGD5-AS1 promotes PC progression and M2 macrophage polarization. Increased transcriptional activity and STAT3 acetylation result from FGD5-AS1's interaction with p300. These findings suggest that FGD5-AS1-rich exosomes are released by PC cells which induces M2 phenotype polarization and promotes aggressive behavior in PC. Targeting exosomal FGD5-AS1 could have diagnostic and therapeutic implications for PC [99] (Table 1).

3.3.2 Reprogramming macrophage phenotype through TAMs-preferentially expressed targets

The Macrophage Receptor with Collagenous Structure (MARCO) is predominantly expressed on M2 phenotype in the TME, which is associated with an immunosuppressive gene profile [100]. The presence of anti-inflammatory cytokine IL-37 and a higher concentration of regulatory T cells are associated with TAMs expressing MARCO. It is also linked to a decline in the quantity of NK cells and a decrease in CD8+ T cell activity [101]. In preclinical studies using murine models of melanoma, breast cancer, and colon cancer, the use of mAbs targeting MARCO has shown promising results. It led to a reduction in tumor growth and impaired metastasis [102]. According to Shi et al., PC cells showed a significant increase in the presence of M2 macrophages. They demonstrated an elevated expression of both MARCO and CD163 in PC cells when compared to adjacent para-cancerous tissues. Moreover, there was considerable variation in the levels of CD163 and MARCO expression among different cases of PC, indicating a heterogeneous expression pattern of these two markers among patients. Additionally, the elevated expression of MARCO and CD163 had a negative impact on both overall survival rates and disease-free survival in patients with PC. More analyses confirmed that expression of MARCO and CD163, independently served as indicators of PC prognosis [103]. Moreover, Sarhan et al., showed that using antibodies directed against MARCO repolarizes myeloid cells toward a pro-inflammatory phenotype, preventing them from suppressing T cells and NK cells through processes that include the release of extracellular ATP, the activation of inflammasomes, and the production of IL-18 [104]. Researchers have identified overexpression of endocannabinoid receptor-2 (CB-2) on TAMs and monoacylglycerol lipase (MGLL) in PC cells. A reduction-responsive nanoplatform has been created by them to co-deliver CB-2 siRNA and MGLL siRNA. This nanoplatform repolarized TAMs into a tumor-inhibiting phenotype and also efficiently inhibited the formation of free fatty acid in PC cells. In xenograft and orthotopic PC tumor models, this approach achieved an anticancer effect by inhibiting nutrient supply and inducing TAMs to secrete tumoricidal cytokines [105]. A recent study uncovered the mechanism by which exosomal miR-193b-3p generated from M2 macrophages promotes the glutamine uptake, migration, proliferation, and invasion of PC cells. This impact was achieved by targeting TRIM62, leading to a decrease in c-Myc ubiquitination. These results shed light on the interaction between PC cells and M2 macrophages and suggested a potential therapeutic target for PC [106].

3.4 Function-based reprogramming

3.4.1 Targeting phagocytic activity of macrophages

Tumor cells have the ability to evade phagocytosis by exploiting MHC I molecules through their interaction with members of the leukocyte immunoglobulin-like receptor subfamily B (LILRB) family. LILRB1, a protein that binds to MHC molecules, is extensively expressed on immune cells and is particularly abundant on TAMs. An inhibitory signal is transmitted by the immunoreceptor tyrosine-based inhibition motif (ITIM) contained in LILRB1. The expression of LILRB1 has been associated with the inhibition of cancer cell phagocytosis. Research on cancer cell lines resistant to anti-CD47 antibodies revealed its function as a myeloid checkpoint. It was found that tumor cells' production of MHC I molecules correlated with their resistance to anti-CD47 therapy. Additionally, inhibiting LILRB1 with particular antibodies could reverse the phagocytic activity that the anti-CD47 antibody had induced [107]. Additionally, macrophages express LILRB2, and blocking it resulted in enhanced phagocytic activity increased and pro-inflammatory activation [108]. The goal of ongoing research is to identify binding partners for LILRB molecules in order to create novel therapies that target macrophages. These binding partners are expected to provide a means of controlling the tumor's ability to evade phagocytosis. In this context, a human monoclonal antibody called MK-4830, which specifically targets LILRB2, has been evaluated in a phase I dose-escalating study for the treatment of advanced-stage solid tumors [109]. The study assessed the antibody both as a monotherapy and in combination with pembrolizumab. Initial findings from the study have shown promising outcomes, with durable responses observed. These results lend credence to MK-4830’s continued exploration as a potential therapeutic agent. Furthermore, it has been reported that the LILRB4 gene plays a critical role in influencing the clinical outcomes of early-stage PDAC and is strongly correlated with the prognosis of these patients [110] (Fig. 2). CD47 is a commonly found protein in various cells and plays a regulatory role in several biological processes, including cytokine production, cell migration, T cell activation, and axon extension [111]. Also, High expression of CD47 has been observed in a variety of tumor types [112]. CD47 has an interaction with signal regulatory protein-α (SIRPα), also referred to as SHPS1, and thrombospondin 1. Through its interaction with SIRPα, CD47 is involved in metastasis, tumor invasion, and, most significantly, the innate immune system's regulation of phagocytosis [112]. These interactions primarily occur with myeloid cells, among them macrophages and DCs. The interaction between SIRPα, which is expressed on macrophages, and CD47, which is expressed on cancer cells, prevents phagosome formation and, consequently, prevents macrophages from engulfing cancer cells. It has been shown that CD47 antagonists enhance the phagocytic ability of macrophages to uptake cancer cells. They additionally promote the presentation of antigens, which increases T cell cross-priming [113]. CD24 is a molecule anchored to the cell membrane by a glycophosphatidylinositol linkage, and it plays a significant role in cancer development [114]. CD24 exhibits remarkably high expression levels at the transcript level across various tumor types, particularly in triple-negative breast cancer (TNBC) and ovarian cancer, and this overexpression is associated with an unfavorable prognosis [115]. Additionally, CD24 participate in regulating important cellular processes including cell proliferation, migration, and invasion [116]. Furthermore, CD24 is considered a potential marker for CSCs [117], indicating its involvement in tumor progression and resistance to therapy. A recent discovery has provided insight into the role of CD24 in inhibiting macrophages [115]. It has been demonstrated that CD24 acts as an immune checkpoint by interacting with Siglec-10, which is TAMs, leading to the suppression of phagocytosis. This interaction establishes CD24 as a novel “don’t eat me” signal in the context of cancer. The expression of PD1 by TAMs has been found to suppress phagocytosis and hinder tumor immunity [118]. This challenges the conventional understanding of the PD1-PDL1 axis as a T cell-specific checkpoint. Simultaneously, the expression of PDL1 on cancer cells enables them to evade both T cell cytotoxicity and macrophage-mediated phagocytosis. Therefore, blocking this axis may potentially unleash anticancer immunity through both innate and adaptive mechanisms. The precise mechanism through which PD1 engagement on macrophages inhibits phagocytosis and the signals that induce PD1 upregulation are yet to be fully understood [119].

Fig. 2
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Different stages of pancreatic cancer

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Several studies have employed Anti-CD47/SIRPα antibodies, including Hu5F9-G4 and BI 765063. Researchers have also shown interest in CD47-Fc fusion proteins, such as TTI-622, TTI-621, IMM-01, SL-172154, and ALX148. Several antibodies [120] and antibody fusions have been developed to target CD24, such as those conjugated with CD30 or CD20 [121]. For patients with metastatic melanoma, a clinical trial is presently being conducted to evaluate the safety and efficacy of combining ipilimumab, nivolumab, and the recombinant fusion protein CD24Fc [122]. The evaluation of combining anti-PD1 or anti-PDL1 therapies with other strategies, such as PI3Kγ inhibitors [82] and TLRs [123, 124] agonists, has been conducted.

3.4.2 Targeting the immunosuppressive and immunostimulating activity of macrophages

A subset of macrophages express SIGLEC1, sometimes referred to as sialoadhesin or CD169, which has been reported to be elevated in some cancers. Its expression levels are correlated with a poorer prognosis [80, 125]. Depletion of CD169+ TAMs was found to be beneficial in lowering tumor burden and metastasis in animal models of breast cancer. Furthermore, the depletion of CD169+ macrophages has been shown to reduce lung metastasis and tumor growth in mouse models of TNBC [126]. The underlying mechanism involves a notable proliferation of CD8+ T cells in the spleen and circulation, in addition to a heightened concentration of these T cells inside the tumors. When CD169+ macrophages were cultivated with tumor cells in vitro, PDL1 was found to be upregulated in the macrophages. This implies that TAMs in the TME might be involved in evading T cell-mediated immune surveillance [80]. A class of small non-coding RNAs known as miRNAs is involved in sequence-specific regulation of transcription and translation. The maturation process of miRNAs is controlled by the enzyme DICER, which belongs to the RNase-III family [127]. A recent study demonstrated that blocking the activity of DICER in macrophages has an impact on the programming of TAMs. This inhibition resulted in tumor regression and modified immune cell infiltration. The inhibition of DICER led to the reprogramming of TAMs, causing them to express an IFNγ-STAT1 signature and exhibit an antitumoral phenotype. Additionally, the inhibition of DICER in TAMs was found to enhance the response to immunostimulatory antibodies, suggesting a potential therapeutic target (benefit) [128]. Several antigen-presenting cells (APCs), including as macrophages, monocytes, B cells and DCs, express CD40, a member of the TNF receptor superfamily. The primary cells that express CD40 Ligand (CD40L) are mast cells, basophils, and CD4+ T cells [129]. MHC molecules are upregulated as a result of the interaction between CD40 and CD40L, and pro-inflammatory cytokines, such as IL-12, are produced. This interaction is essential in order to prime naïve CD4+ and CD8+ T cells and direct their differentiation into Th cells and cytotoxic cells, respectively. Targeting CD40, a number of therapeutic approaches have been developed, including agonistic CD40 antibodies, recombinant human CD40L and its fusion proteins, and CD40L gene therapy using adenoviral vectors expressing CD40L. Notably, the administration of CD40 agonists to TAMs in conjunction with anti-CSF-1R antibodies leads to a significant reprogramming of TAMs prior to their depletion. These reprogrammed TAMs help foster an environment that is pro-inflammatory and stimulates potent T cell responses. Importantly, this approach has shown promise in eliciting T cell responses in tumors that were previously unresponsive to immune checkpoint inhibitors [130, 131].

There are ongoing clinical trials investigating at least ten therapeutics that target CD40. Some of these therapeutics have progressed to phase 2 trials, including ChiLob7/4, which is being evaluated for the management of head and neck cancer and PC [132]. Also, another clinical trial has been conducted to evaluate the combination of CP870,893 and Gemcitabine for patients diagnosed with newly resectable PC [133]. In addition, CP-870,893 in combination with gemcitabine demonstrated favorable tolerability and showed indication of anti-tumor efficacy in PDAC patients [134]. APX005M has recently obtained FDA approval as an orphan drug for the treatment of PDAC, esophageal and gastroesophageal junction cancer [135, 136]. RO7009789 is another anti-CD40 antibody that has been evaluated on PC [137].

3.4.3 CAR macrophage

There have been advancements in utilizing macrophages that express chimeric antigen receptors (CARs) to target particular molecules including CD47 and CSF-1R. These approaches aim to enhance immune responses by directing to SIRPα-expressing macrophages. This targeted amplification of immune responses has shown promise in limiting tumor growth [138, 139]. CAR-macrophages (CAR Ms) have been found to express proinflammatory cytokines and chemokines, enabling them to recruit immune cells and present antigens to T cells. To summarize the process of developing and using CAR Ms, monocytes are stimulated through subcutaneous administration of G-CSF before being isolated through leukapheresis and CD14+ monocyte selection. These monocytes are then cultured to differentiate into macrophages and genetically modified with Adf535, which encodes the CAR transgene. Subsequently, the CAR M cells are cryopreserved in a suitable medium for infusion and undergo testing to ensure their quality before being used in therapy [140, 141] (Fig. 3). Remarkably, a single infusion of human CAR Ms improved overall survival and reduced tumor burden in two tumor xenograft mouse models [140]. The efficacy of adenovirus-transduced macrophages expressing an anti-HER2 CAR is currently under evaluation in a clinical investigation [142].

Fig. 3
figure 3

Development of CAR Macrophages from induced pluripotent stem cells (iPSCs) and their mechanism of action

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3.5 Targeting macrophage recruitment

Recruitment of circulating monocytes replenishes the TAMs population on a continual basis. Preventing the recruitment of new TAMs is another method for lowering the total number of TAMs within a tumor. Due to the involvement of the chemokine CCL2 in the recruitment of monocytes to tumors, significant research has focused on targeting the CCL2/CCR2 axis [78]. Several investigations have demonstrated that in a variety of tumor models, reducing CCL2 signaling through the use of neutralizing antibodies or small-molecule inhibitors can result in a decrease in tumor size and metastases [143,144,145]. However, despite promising results in preclinical models, clinical trials investigating CCL2/CCR2 blockade have not shown comparable efficacy [146]. Studies indicate that CCL2 may serve as a significant negative regulator of PC progression. While there was an inverse relationship between blood CCL2 levels and tumor proliferative activity, a positive association was established in PC patients between serum CCL2 levels and TAM infiltration [147]. Patients with tumors displaying high CCL2 expression and low CD8 T-cell infiltration experience notably reduced survival rates. In mouse models, inflammatory monocytes and macrophages from the main tumor and premetastatic liver are efficiently reduced by inhibiting CCR2. This depletion subsequently enhances antitumor immunity, reduces tumor growth, and diminishes metastasis [148]. TAMs generate TNF-α, which inhibits PDAC cells’ production of IL-33. In mouse models, TNF-α was decreased and IL-33 expression was up when monocyte recruitment was inhibited by CCR2 deletion, which enhanced survival and decreased metastases. High CCL5 levels in the TME aid in the accumulation of macrophages and lymphocytes that have high CCR5 expression levels. Apart from its part in immune cell recruitment, CCL5 is involved in various processes, including tumor growth, drug resistance, expansion of CSCs, invasion of cancer cells, promotion of neoangiogenesis, and polarization of macrophages towards an immunosuppressive phenotype [149]. CXCL12 is a chemokine that is involves in regulating the migration of monocytes and angiogenesis [150, 151]. Targeting the angiogenic and chemotactic factor CXCL12, which signals through CXCR4, has been explored as a strategy to decrease TAMs infiltration [151].

Phase I clinical studies have been initiated for a number of therapeutic agents that target the CCL2/CCR2 pathway, such as small-molecule inhibitors and mAbs. These include the CCL2-neutralizing antibody CNTO888 (Carlumab) [152], and the anti-CCR2 antibody MLN1202 (plozalizumab) [153]. PF-4136309 which is a CCR2 antagonist have been evaluated on PDAC in combination with gemcitabine and Nab-paclitaxel [154]. At the suggested phase 2 dosage, PF-04136309 plus FOLFIRINOX did not result in any additional toxicity. Blockade of CCR2 resulted in a reduced infiltration of TAMs and demonstrated signs of an innate anti-tumor immune response. These findings indicate that CCR2-targeted therapy has an impact on the biology of PDAC [155]. A phase 1-b open-label study assessing the safety and efficacy of CCX872-B (a CCR2 antagonist) in patients with PDAC who were receiving FOLFIRINOX chemotherapy has been successfully completed [156]. They reported that combination of CCX872-B and FOLFIRINOX produced an 18-month overall survival rate of 29% without any safety concerns. Additionally, the treatment resulted in a decrease in circulating monocytes, inflammatory monocytes, and monocytic MDSCs [157]. By using CCX598, an orthosteric inhibitor, to target CCR2, PDAC became susceptible to checkpoint blocking, which decreased metastasis and improved survival. These findings suggest that disrupting immunosuppressive macrophage infiltration or their signaling could enhance immunotherapeutic efficacy for PDAC by promoting antitumor immunity mediated by IL-33, cytotoxic T cells, and DCs [158]. In preclinical studies conducted on mouse models of PC and prostate cancer [159, 160], the use of CCR5 antagonists demonstrated a reduction in tumor growth, as well as a decrease in tumor adhesion and invasion. The effectiveness of BMS-813160, an CCR2/CCR5 antagonist, either as a standalone treatment or in combination with chemotherapy, nivolumab, or chemotherapy plus nivolumab, has been evaluated in participants with metastatic CRC and PC [161]. In a clinical trial, the efficacy of treatment involving a CCR5 antagonist, Maraviroc, aCCR5 antagonist, in combination with nivolumab and ipilimumab, was investigated in patients with CRC and PC [162, 163]. The interaction between CCR5 and CCL5 has been identified as a potential indicator for metastatic PC, as it contributes to heightened invasion of PC cells [150]. Plerixafor (AMD3100) is one of the CXCR4 antagonists, which was approved in 2008 for autologous transplantation for the mobilization of hematopoietic stem cells. Currently, it is under investigation in clinical trials for its potential use in various types of cancers [164]. BL-8040 (motixafortide), a CXCR4 antagonist, demonstrated effectiveness when used in combination with pembrolizumab and chemotherapy in PDAC [165]. Moreover, the cooperation between CXCL8/IL-8 and CXCL12/stromal cell-derived factor-1α can enhance migration, invasion, and angiogenesis. This suggests that targeting CXCR2 (the receptor for CXCL8) and CXCR4 (the receptor for CXCL12) could serve as potential therapeutic targets for anti-angiogenic and anti-metastatic strategies in PC [151]. Plerixafor (AMD3100) is also a CXCR4 antagonist which had promising results in clinical trials (Table 1).

4 Challenges and limitations of targeting macrophages in PC

PC exhibits a higher level of aggressiveness compared to other gastrointestinal malignancies, primarily due to its early-stage dissemination through hematogenous or lymphatic metastasis. This aggressive behavior is linked to poor prognosis and challenging therapeutic options. Firstly, while the field of cancer research and therapy has witnessed rapid progress in targeting macrophages as a potential treatment option, determining the optimal therapeutic approach remains a challenge due to the heterogeneous nature of TAMs and their diverse roles influenced by environmental conditions. It was reported that pancreatic TME is highly heterogeneous, as this heterogeneity could influence the efficacy of future PC treatment [166,167,168]. Generally, TAMs numerates as the most abundant tumor-infiltrating immune cells in PC, which are divided into two subgroups including immune-stimulatory macrophages (M1) and immunoregulatory macrophages (M2) [166]. The ability of macrophages to switch between two pro-inflammatory and anti-inflammatory states has a dynamic characteristic and plays a significant role in the progress and development of PC [169]. Pan et al. [170] reported that the increase in the abundance of CD68+ macrophages and CD163+ M2 in tumors was significantly associated with worse survival in patients with PC. Chen et al. [171] reported that SPP1, as an immune-related marker, is mainly expressed in type 2 ductal cells and M2 macrophage in PC. Moffitt et al. [172] reported two tumor cell subtypes (“basal-like” and “classical” and two stromal subtypes (“normal” and “activated”) for PDAC. It was found that tumors with “basal-like” subtype presented a worse prognosis compared to either corresponding subgroup but additionally it seems that this subtype shows better responses towards adjuvant therapy. Bailey et al. [173] performed a genomic analysis and identified 4 subtypes including squamous; pancreatic progenitor; immunogenic; and aberrantly differentiated endocrine exocrine (ADEX). Therefore, it seems that the identification of these differences provides opportunities for therapeutic development [174].

Secondly, the dynamic TME, comprising infiltrating immune cells and external factors, further complicates the matter. Thirdly, recognizing tumor heterogeneity and its evolution during the transition to malignancy and post-therapy becomes crucial in comprehending the TAMs and other immune cells' dynamic interactions [80]. The effects of these interactions vary based on the stage of progression and cancer type.

Furthermore, as mentioned earlier, numerous studies have explored the combination of macrophage therapy with conventional treatments for PC and other cancers. It is worth noting that the success of combination therapy requires a comprehensive comprehension of the TME, including the heterogeneity of macrophage populations and their interactions with other immune cells. Compared to mouse PC tumors, human PC tumors show a higher degree of interpatient, intertumor, and intratumor heterogeneity altogether between individuals [172, 173, 175,176,177,178,179]. Therefore, designing treatment options with the approach of targeting macrophages will not be successful without understanding the complex system related to the PC TME and will have deleterious or negligible clinical outcomes. Finally, careful consideration should be given to the timing, dosing, and sequencing of treatments to maximize their synergistic effects and minimize potential adverse effects. For instance, depletion strategies, like CSF-1R inhibitors, have shown potential efficacy but pose the risk of non-specific depletion of monocytes and macrophages, leading to long-term toxicity [63, 78]. Plus, the complexity of TAM populations highlights the essential functionality of DCs and macrophages in the effectiveness of specific therapies, such as anti-PD1 and anti-CTLA4. Another example is careful timing and a comprehensive understanding of immune interactions throughout different tumor formation stages, which are crucial for successful implementation of Fcγ receptor inhibitors.

5 Emerging research and future directions

PC, the twelfth most common cancer worldwide, is associated with an extremely poor prognosis and survival rate. While resection offers a potential cure for patients with PC, 20% of patients are candidates for resection at the time of diagnosis, and despite the surgery, most of the patients die due to local recurrence or metastasis. It was estimated that the 1-year disease-related mortality is 30% [180,181,182]. Therefore, it is meaningful to reduce the tumor stage and improve the resectable rate through neoadjuvant therapy [183,184,185]. Given the various ways in which macrophages promote the development and progression of PC, they are considered as potential targets for anti-cancer treatment. Macrophages play a crucial role in cancer progression and have emerged as potential therapeutic targets. Some potential new targets and strategies for modulating macrophage function include inhibition of monocyte/macrophage recruitment, killing or depletion of macrophages, reprogramming of macrophage phenotypes at disease sites, inhibition of cytokines and chemokines involved in the recruitment and polarization of tumor-promoting macrophages, targeting macrophage receptor-ligand interactions, modulating macrophage polarization, chimeric antigen receptor macrophage therapy, and macrophage-mediated drug delivery systems. Some of the macrophage-targeting therapies are currently undergoing clinical evaluation, and there is growing interest in understanding how targeting different macrophage populations can affect immunosuppression, fibrosis, and responses to chemotherapy [186]. Macrophage-derived CCL18 has been shown to enhance the invasive ability of PC cells, and targeting this pathway could potentially impact tumor progression [187]. The use of chimeric antigen receptor (CAR) macrophages showed that in situ CAR engineering of macrophages with MUC1-specific CARs stimulated tumoricidal immunity against pancreatic adenocarcinoma [188]. CAR-engineered macrophages induced a shift in the TME from an immunosuppressive to a tumoricidal state, supporting the potential of applying CAR macrophages in the TME in pancreatic adenocarcinoma. Investigating the role of M2 macrophage-derived exosomes in PC progression demonstrates that exosomal miR-193b-3p, derived from M2 macrophages, enhances the proliferation, migration, invasion, and glutamine uptake of PC cells by targeting TRIM62, leading to a decrease in c-Myc ubiquitination. These findings provide insights into the mechanism involved in the crosstalk between M2 macrophages and PC, and shed light on the potential impact of targeting this pathway for the treatment of PC [106]. In another miRNA-based strategy, the role of miR-222-3p-containing extracellular vehicles (EVs) derived from M2 macrophages in conferring gemcitabine resistance in PC was evaluated by co-culture of PC cells with M2 macrophage-derived EVs enriched with miR-222-3p, which led to decreased sensitivity to gemcitabine, lower percentage of apoptosis and enhanced proliferation. Furthermore, the delivery of a miR-222-3p inhibitor by M2 macrophage-derived EVs suppressed tumor growth and elevated the sensitivity of cancer cells to gemcitabine. miR-222-3p also targets and suppresses TSC1 expression, while activating the PI3K/AKT/mTOR pathway, thereby contributing to gemcitabine resistance in PC, suggesting the potential of targeting miR-222-3p and the associated pathways as a therapeutic strategy to overcome gemcitabine resistance in PC [189]. Studying the impact of blocking the CCR4 chemokine receptor on intratumoral macrophage recruitment and survival in PC bearing mice demonstrated that defeat in the CCR4 chemokine receptor or blockade of CCR4 in mice exerted a significant survival benefit in PC bearing mice. Diminished intratumoral macrophage recruitment led to a decrease in tumor growth and an increase in survival rates, suggesting that the CCR4 chemokine receptor blockade may be a potential therapeutic approach for PC, as it reduces the recruitment of macrophages to the TME and enhances the survival of cancer-bearing mice [190]. Evaluation of the effect of the ALOX5 enzyme inhibitor (Zileuton) in regulating TAM polarization and its impact on PC invasion and metastasis showed regulated TAM M2 polarization by targeting the JAK/STAT pathway. The findings demonstrated that Zileuton inhibited PC invasion and metastasis by suppressing M2 TAM polarization [191]. Applying the combination of an mTOR inhibitor, gemcitabine, and a PD-L1 antibody on PC progression in Trp53flox/+LSL-KrasG12D/+Pdx-1-Cre murine models showed suppressed PC progression by inducing metabolic reprogramming and remodeling the immune microenvironment. mTOR inhibition could change the immune microenvironment of PC via metabolic reprogramming, and promoting the efficacy of PD-L1 blockade when combined with gemcitabine [192]. In another study, the role of arginase 1 (Arg1) in driving immune suppression in PC was evaluated and showed that Arg1 drives immune suppression in PC by depleting arginine and inhibiting T cell activation. Also, genetically inactivation of Arg1 in macrophages in a dual recombinase genetically engineered mouse model of PC led to delayed invasion and higher rate of CD8+ T cell infiltration. An arginase inhibitor designated CB-1158 was applied to treat established tumors. The results exhibited that there was an additional increase in CD8+ T cell infiltration beyond what was observed with the macrophage-specific knockout, and the tumors acquired more sensitivity to anti-PD1 immune checkpoint blockade. The research highlights the potential of targeting Arg1 as a promising immunotherapeutic target to enhance the response to immune therapy in PC [193]. Moreover, high CXCR4+ macrophage infiltration is associated with poor overall survival and disease-free survival in PDAC patients. Targeting CXCR4+ macrophages is a potential therapeutic strategy to improve the prognosis of PDAC patients since CXCR4+ macrophages promote PDAC progression by inducing immune suppression and remodeling the TME [194]. While macrophage-targeting therapies hold promise, there are also clinical challenges associated with these treatment modalities in human PDAC patients. The desmoplastic stroma which provides an immunosuppressive microenvironment with a dense barrier to protects tumor cells from immunological elimination and prevent penetration of chemotherapeutics, poses a significant obstacle to the development of therapies. Overcoming these challenges will require a deep understanding of the complex interactions between macrophages, the TME, and the immune system [195].