Macrophage-centered therapy strategies: A promising weapon in cancer immunotherapy

Simiao Wang; Jiayi Liu; Yaxin Cui; Man Sun; Wei Wang; Jiayi Chen; Jingkai Gu; Zhaogang Yang

doi:10.1016/j.ajps.2025.101063

. 2025 Apr 29;20(5):101063. doi: 10.1016/j.ajps.2025.101063

Macrophage-centered therapy strategies: A promising weapon in cancer immunotherapy

Simiao Wang ^a,¹, Jiayi Liu ^a,¹, Yaxin Cui ^a,¹, Man Sun ^a, Wei Wang ^b, Jiayi Chen ^a,^⁎, Jingkai Gu ^a,^⁎, Zhaogang Yang ^a,^⁎

PMCID: PMC12552155 PMID: 41809255

Abstract

Macrophages are critical phagocytes in the immune system, and tumor-infiltrating macrophages can substantially influence the efficacy and prognosis of immunotherapy. Therefore, macrophages may serve as therapeutic targets for modulating the tumor immune microenvironment. Macrophage-based drug delivery systems have been extensively evaluated owing to their excellent biocompatibility, long half-life, and inherent ability to migrate and accumulate at sites of inflammation, such as tumors. Live macrophages and their membrane coatings contain abundant receptor proteins that facilitate payload transport across physiological barriers. In this review, we discuss strategies that utilize macrophages as targets and delivery carriers for cancer immunotherapy. Here, we summarize the different macrophage phenotypes, tumor-associated macrophage-targeting strategies, and biomimetic delivery carriers derived from macrophages used in immunotherapy. Overall, macrophage-centered strategies for cancer therapy hold considerable promise for clinical applications.

Keywords: Macrophages, Immunotherapy, Drug delivery system, Membrane coatings, Extracellular vesicles

Graphical abstract

Therapeutic strategies targeting TAMs are regarded as one of the most promising research strategies against tumor. At present, strategies for targeting TAM mainly include the inhibition of “don't eat me” signaling at phagocytic checkpoints, inhibition of macrophage recruitment, depletion of TAMs and reprograming TAMs in TME.

1. Introduction

Cancer is a leading cause of death worldwide, with the American Cancer Society projecting nearly 2 million new cancer cases and 610,000 cancer-related deaths by 2024 [1]. Despite recent advancements in early cancer detection and treatment, reductions in cancer mortality rates remain modest, owing to the complex heterogeneity of malignant tumors. Consequently, there is an urgent need to develop innovative anticancer therapies with superior efficacy [2]. Cancer immunotherapy, which functions by stimulating the body's innate immune system to elicit a tumor-specific immune response, thereby exerting inhibitory and cytotoxic effects on malignant cells [3], represents a groundbreaking therapeutic approach in current medical research [[4], [5], [6], [7]]. Unlike conventional treatments such as surgery, radiotherapy, and chemotherapy, the fundamental principle of tumor immunotherapy lies not in direct cancer cell eradication but rather in indirectly reinstating the capacity of immune cells to recognize and suppress neoplastic growth [8]. However, despite achieving state-of-the-art and promising efficacy in clinical trials, challenges persist, including immune cell dysfunction or systemic immunotoxicity induced by the immunosuppressive tumor microenvironment (TME) [9], suboptimal immune response activation rates [10], and severe clinical side effects [11].

To improve the therapeutic outcomes of immunotherapeutic drugs and address challenges such as short half-life, limited tumor penetration, high toxicity, and numerous side effects, various drug delivery systems (DDSs) have been developed and evaluated [12]. Among these approaches, nano-DDSs have garnered considerable attention owing to their unique composition and excellent biocompatibility [13]. However, exogenous nanoparticles (NPs) are recognized as “invaders” by the body's immune system upon administration, undergoing subsequent clearance by the mononuclear phagocytic system, which hinders their deep penetration into tumors [14]. Therefore, biomimetic drug delivery carriers developed by modifying synthetic NPs or genetic engineering have emerged as promising alternative strategies.

Macrophages are the predominant immune cell population within the TME and are critical for regulating both innate and adaptive immune responses [15]. As proficient antigen-presenting cells (APCs), macrophages can specifically bind to tumor cells, phagocytose and degrade pathogens [16], and activate lymphocyte-mediated adaptive immune responses [17]. Furthermore, macrophages express a variety of surface receptors, including chemokine receptors such as C-X-C motif chemokine receptor 4 (CXCR4), C—C motif chemokine receptor 2 (CCR2) and CCR5, integrins (like αvβ3 and α4β1), immune checkpoints, and phagocytosis receptors. These receptors facilitate macrophage infiltration into tumor sites by binding to their respective ligands, enhancing tumor specificity and ultimately contributing to the eradication of tumor cells [18]. Therefore, capitalizing on the inherent characteristics of macrophages, live macrophages cultured in vitro have been used as an innovative DDS for the targeted delivery of immunotherapeutic antibodies and small-molecule drugs, demonstrating exceptional efficacy [19]. Moreover, by leveraging the membrane-coating technique of erythrocyte membranes encapsulated poly (lactic-co-glycolic acid) (PLGA) NPs [20], macrophage membranes encapsulating nanoporous silica particles have been developed to evade immune system clearance [21]. Subsequently, the utilization of primary tumor-associated macrophage membranes (TAMM) [22], along with the development of chimeric antigen receptor-macrophage (CAR-M) therapeutics, has demonstrated improved tumor-homing and antitumor effects [23]. Additionally, phagocytic checkpoints on the surface of macrophages, such as CD47/signal regulatory protein α (SIRPα) [24], on the macrophage surface have been shown to play a critical role in immunotherapy. Given that M1 and M2 macrophages possess antitumor and pro-tumorigenic effects, respectively [25], strategies targeting macrophage reprogramming and repolarization, or blocking phagocytic checkpoints, can further enhance the effectiveness of immunotherapy.

Hence, in this review, therapeutic strategies for macrophage-based cancer immunotherapy (Fig. 1), including macrophage targeting and their use as delivery carriers, are comprehensively discussed. Specifically, an overview of the origin and immunophenotyping of macrophages is presented, followed by an in-depth examination of therapeutic approaches aimed at modulating macrophages, including phagocytic checkpoint blockade, tumor-associated macrophage (TAM) recruitment inhibition, TAM depletion, and TAM reprogramming. Subsequently, the application of live macrophages as delivery vectors, along with techniques such as cell membrane coating for biomimetic NP construction, CAR-M therapeutic implementation, and extracellular vesicles (EVs) derived from macrophages, have been elucidated.

2. Phenotype of macrophages

2.1. Origin of macrophages

Macrophages have long been recognized as crucial immune effector cells owing to their notable role in the immune response. They are ubiquitous in almost all healthy individuals and originate from two primary sources. A minority of macrophages are derived from prenatal embryonic precursors (yolk sac or fetal liver), where they are maintained in an active state via the self-renewal of adult tissue-resident macrophages (TRMs) [26], while the majority originate from hematopoietic stem cells (HSCs) within the spinal cord [27]. Upon stimulation with macrophage colony-stimulating factors, HSCs undergo division and differentiation into monoblasts [28], which subsequently mature into pro-monocytes and eventually develop into monocytes [29].

Within the bloodstream, monocytes develop into tissue-specific macrophages such as osteoclasts (skeletal system), microglia (central nervous system), alveolar macrophages (AMs; lungs), Kupffer cells (KCs; liver), and histiocytes (connective tissues) [30,31] (Fig. 2). Macrophages exhibit considerable tissue heterogeneity and perform distinct physiological functions during development.

Fig 2 — Biogenesis and phenotype plasticity of macrophages.

Although macrophages develop and mature in specific tissues, their functions are largely predetermined upon exiting the bloodstream. Two distinct types of monocyte-derived macrophages have been identified in mouse blood, each exhibiting diverse phenotypes and characteristics. The classification of monocytes depends on the duration of their presence in the bloodstream before their migration into tissues. GR1+CX3C chemokine receptor 1(CX3CR1) low monocytes, also known as “inflammatory” monocytes, rapidly exit the bloodstream. In contrast, GR1- monocytes, also termed “resident” monocytes, remain in the bloodstream longer and differentiate into other subgroups [32]. Notably, considering the disparities in physiological functions and subpopulations between mouse and human monocytes, there are variations in both the classification methods and subpopulation ratios of these cells. Based on the differential expression of CD14, CD16 (Fcγ RIII), CD64 (Fcγ RI) and chemokine receptors (including CD192 and CX3CR1), as well as the stimulatory conditions of various cytokines and chemokines, the monocyte-macrophage population is defined as two different subpopulations: classically activated macrophages (M1) and selectively activated macrophages (M2) [32] (Fig. 3 and Table 1). Beyond this activation-based classification, macrophages exhibit notable tissue heterogeneity, leading to the identification of various subtypes, with TAMs and TRMs being the most representative [32,33].

Fig 3 — Classification of macrophages under cytokines and chemokines stimulations.

Table 1.

M1 macrophage and M2 macrophage classifications.

	Stimulation	Markers	Cytokines	Chemokines	Function	Drawback
M1	GM-CSF, TNFα, LPS, IFN-γ	CD86, CD80, CD68, TLR4, iNOS, SOCS3, MHC II, IL-1R, TLR2	High TNFα, IL-1β, IL-18, IL-23, IL-6, IL-12	CXCL1, CXCL3, CXCL5, CXCL8, CXCL9, CXCL10, CXCL11, CXCL13, CXCL16, CX3CL1, CXCR3, CCL2, CCL3, CCL4, CCL5, CCL8, CCL11, CCL15, CCL19, CCL20, NOS2, CD64, IDO, SOCS1	Pro-inflammatory activity Tissue damage Production of inflammatory cytokines Anti-bacterial Antitumor immunity Host defense	Pro-inflammatory overload leads to tissue damage and cytokine storm production
M2a	IL4, IL13	CD68, CD206, YM1/2, FIZZ1, Arg-1	IGF, IL-10, sIL-1R	CCL17, CCL18, CCL22, CCL24	Enhance endocytic activity Promote cell growth Promote tissue repair Anti-parasitic & Allergic responses	Anti-inflammatory overproduction of immune tolerance leads to tissue fibrosis and promotes cancer development
M2b	LPS, Immune complex, IL-1R/TLR ligands,	CD86, IL-6R, IL-10R, IL-12R, MHC II	IL-1β, IL-6, IL-10, NF-α	CCL1, CCL20, CXCL1, CXCL3	Promote Th2 differentiation Promote parasitic and bacterial Promote fungal infections Inflammatory reactions
M2c	Glucocorticoids, IL-10, TGF-β	CD163, CD206, TLR-1, TLR-8	IL-10, TGF-β	CXCL13, CCL16, CCL18, CCR2	Anti-inflammatory Immunoregulation Phagocytosis of apoptotic cells
M2d	IL6, TLR agonists	IL-10R, IL-12R	IL-10, GF-β, VEGF	CXCL10, CXCL16, CCL5	Promote tumor progression Angiogenesis Metastasis

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2.2. Classically activated macrophages

Classically activated macrophages (M1), also known as inflammatory macrophages, are induced alone by interferon-γ (IFN-γ), which is released by natural killer (NK) cells, Th1 cells, and cytotoxic T lymphocytes (CTLs), or in combination with tumor necrosis factor (TNF-α) and bacterial lipopolysaccharide (LPS) [34]. M1 macrophages possess enhanced antigen-presenting capacity because they can produce pro-inflammatory factors, including interleukin (IL)-1β, IL-6, IL-12, IL-23, TNF-α, CCL5, chemokines such as C-X-C motif chemokine ligand 9 (CXCL9), CXCL10, CXCL11 and CXCL16, as well as reactive oxygen species (ROS) and nitric oxide synthase (NOS) [34]. They also secrete intracellular proteins such as NOS2 and suppressor of cytokine signaling 3 (SOCS3) [35]. On their cell membrane, M1 macrophages predominantly express major histocompatibility complex class II (MHC-II) [15] and CD markers (CD86 and CD80), as well as other markers such as inducible NOS (iNOS), toll-like receptor-2 (TLR-2), and TLR-4.

As these molecules are critical for the innate immune response, M1 macrophages actively participate in type I immune responses. The primary function of the M1 type is the clearance of pathogens, dead cells, and foreign bodies [36], which is mainly dependent on the activation of the nicotinamide adenine dinucleotide phosphate oxidase system and ROS production [37]. Additionally, M1 macrophages exhibit robust antitumor activity, relying on glucose-to-lactate fluxes, ROS, and NO production to kill tumor cells [38]. They also mediate ROS-induced tissue damage, prevent tissue regeneration, and wound healing [39]. Therefore, M1 plays a critical role in anticancer processes. Taken together, classically activated macrophages are closely associated with cell-mediated immune responses and serve as an important line of defense against microbes and pathogens.

2.3. Alternatively activated macrophages

Alternatively activated macrophages (M2) are also known as anti-inflammatory macrophages. The primary factors that activate macrophages to the M2 phenotype are cytokines (IL-4, IL-13, IL-10, and IL-34), vitamin D3, colony-stimulating factor 1 (CSF1), transforming growth factor (TGF)-β, prostaglandin E2 (PGE2), vascular endothelial growth factor (VEGF), endothelial growth factor (EGF), and glucocorticoids [40]. Additionally, they exhibit tumorigenic activity through matrix remodeling, angiogenesis, and tissue repair, thereby facilitating tumor initiation, progression, and angiogenesis [41].

Based on their functions, cellular markers, and physiological characteristics, M2 macrophages were further classified into four subpopulations: IL-4/13-activated M2a, immune complex-activated M2b, IL-10-inactivated M2c, and IL-6/M-CSF loop-induced M2d macrophages [34] (Fig. 3). M2a macrophages secrete various pattern recognition receptors, including CD206, CD209 and Dectin-1, which facilitate the sensing and clearance of invading bacteria, fungi, and parasites [15]. It promotes cell growth, tissue repair, and phagocytosis. Among the other three types, M2b macrophages regulate the immune response and inflammation [42], whereas M2c and M2d play important roles in phagocytosis and tumor progression, respectively [43]. Specifically, M2d macrophages produce pro-tumor factors, suppress normal immune responses, and help tumor cells evade immune surveillance [44]. Although an important target, potent drugs capable of specifically targeting M2d subtypes are lacking, and most therapies target the entire M2 system. Given that each subtype is complementary, a strategy that addresses the entire immunosuppressive TME is even more relevant.

In terms of cellular markers, unlike M1 macrophages, M2 macrophages predominantly express CD163 and CD206, which are mannose receptors that promote macrophage activation, antigen presentation, and immune responses [45,46]. Notably, M2 macrophages exhibit greater sensitivity to CD163, which serves as a specific marker for M2-type macrophages [47] and is closely associated with the proliferation of malignant tumors, including breast, bladder, lung, and colorectal cancers [48]. The extent of CD163 infiltration directly affects tumor proliferation, invasion, metastasis, and prognosis. Overall, M2-like macrophages have been shown to facilitate tumor growth, participate in cancer invasion and metastasis, promote tumor neovascularization, and contribute to the establishment of an immunosuppressive TME [49,50].

2.4. Tumor associated macrophages (TAMs)

TAMs are macrophages that originate from monocytes in the bloodstream, migrate to the tumor site, infiltrate tumor tissues, and perform specific functions. They respond to chemokines secreted by tumor cells, such as CSF1 and C—C motif chemokine ligand 2 (CCL2), which play critical roles in the TME. The role of TAMs in tumor progression is diverse, including the direct inhibition of cytotoxicity in NK and CD8⁺ T cells, as well as the release of NO and reactive oxygen intermediates to counteract the Th1 immune response (Fig. 3) [51,52].

There are two main subtypes of TAMs: M1-like and M2-like. M1-like TAMs are more abundant during the early stages of cancer development and exhibit pro-inflammatory functions [53]. As monocytes continue to express CXCL12, they promote the transition of M1-like TAMs into M2-like TAMs. Unfortunately, in terminal-stage tumors, most TAMs exhibit the M2 subtype. M2-like TAMs exert pro-tumorigenic and immunosuppressive effects through multiple mechanisms. For example: (1) Promotion of tumor cell proliferation: M2-like TAMs can promote tumor cell proliferation and invasion through the direct secretion of growth factors, such as EGF and platelet-derived growth factor [54]; (2) Involvement in tumor invasion and metastasis: M2-like TAMs release pro-tumor cell metastasis factors such as matrix metalloproteinases (MMP; e.g., MMP2 and MMP9), which directly promote cancer cell proliferation, invasion, and migration [55]; (3) Regulation of tumor cell metabolism to promote tumor growth: M2-like TAMs reportedly facilitate aerobic glycolysis, cell proliferation, and tumor growth in glioma cells, thereby promoting the malignant progression of tumors [56]; (4) Involvement in immune escape of cancer cells: M2-like TAMs participate in immune escape regulation of cancer cells via the secretion of factors such as IL-10, PGE2 and TGF-β [57]; (5) Promotion of angiogenesis: TAM-derived VEGF is involved in the development of tumor microvessels and lymphatic vessels and directly mediates angiogenesis in tumor tissues [58]; (6) Resistance to therapy: M2-like TAMs have been shown to reduce the outcome of immune checkpoint blockade (ICB) therapy [59]. For example, TAMs express high levels of programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1), which, upon activation, block the cytotoxic activity of T and NK cells, thereby exerting their immunosuppressive functions [60]. In summary, TAMs contribute to the establishment of a tumor-supportive TME by suppressing the antitumor activity of immune cells.

2.5. Tissue-resident macrophages (TRMs)

TRMs are a specialized class of immune cells originating from monocyte precursors in the yolk sac and fetal liver during embryonic development. They then migrate to various tissues and organs to perform specific immune functions [61].

Although TRMs share some functional similarities with M2 macrophages [62], they are not fully equivalent. Macrophages exhibit distinct phenotypic and functional properties depending on the tissue of residence. For example, in the bone, osteoclasts originating from the hematopoietic monocyte-macrophage system fuse to form multinucleated cells that absorb bone by destroying the mineralized matrix [63]; in the spleen, red-pulp macrophages remove senescent erythrocytes [62]; in the brain, microglia clear dead neurons in neural tissue and facilitate synaptic remodeling [64]; and in the alveoli, AMs help remove inhaled pathogens [65]. In conclusion, TRMs play key roles in maintaining tissue homeostasis, promoting tissue repair [66], mediating inflammatory responses [67], and defending against pathogens [68].

In the context of tumor progression, TRMs exhibit high diversity in their responses to signals in the TME and have considerable plasticity in tumor immunotherapy. In primary tumors, AMs expressing P16 and CXCR1 were shown to inhibit the CTL response and promote lung tumor progression via various signaling pathways, including ROS, BACH1, PDLIM2 and STAT3 [69]. Conversely, INHBA upregulation in AMs triggered the production of activin A, which, in turn, suppressed the growth of lung cancer cells [70]. In addition to their diverse roles in primary cancers, TRMs may contribute to metastatic cancer regulation in a distinct manner. Shang et al. found that regulating the recruitment of monocytic myeloid-derived suppressor cells (mo-MDSCs) via the CXCL10-CXCR3/TLR4-CCL12 axis in AMs is a promising therapeutic approach to inhibit lung metastasis [71]. Wen et al. [72] demonstrated that early depletion of KCs regulates INOS and VEGF, promoting metastatic tumor growth, whereas KC depletion at a later stage increases CD3⁺ cell infiltration, thereby inhibiting tumor metastasis. This suggests that KCs play a bimodal role in tumor development. In addition, the use of TRMs as part of a tumor vaccine could elicit a more effective antitumor immune response. Langerhans cells (LCs), a distinct population of TRMs, express endocytosed C-type lectin receptor CD207. Wamhoff et al. developed a liposome coated with a CD207 mimetic glycan ligand to specifically target LCs [73]. This novel vaccine successfully induced a protective immune response against tumors.

Overall, the potential of TRMs in tumor immunotherapy is gradually being exploited. Through in-depth research and clinical validation, these strategies could provide more effective therapeutic options for patients with cancer.

3. TAM-targeting strategies in tumor immunotherapy

As TAMs constitute the majority of infiltrating immune cells in the TME and play an essential role in tumor immunomodulation, therapeutic strategies targeting TAMs are considered among the most promising approaches for combating tumors [25,74]. Current TAM-targeting approaches mainly include the inhibition of “don't eat me” signaling at phagocytic checkpoints, blockade of macrophage recruitment, depletion of TAMs, and reprograming TAMs in TME, as shown in Fig. 4. Here, we discuss the current status of TAM-targeted strategies and provide an overview of the ongoing clinical trials (Table 2).

Fig 4 — Primary TAM-targeting strategies include: regulation of phagocytic checkpoints, inhibiting macrophage recruitment, depletion of TAMs, and reprograming TAMs.

Table 2.

Clinical trials investigating TAMs as a potential target for cancer treatment.

Targets	Drugs	Type of tumors	Combination partners	Phase	NCT identifier
CD47	Hu5F9-G4	Solid tumors		Ⅰ	NCT02216409
	Hu5F9-G4	B-cell lymphoma	Obinutuzumab venetoclax	Ⅰ	NCT04599634
	Hu5F9-G4	Breast or castrate-resistant prostate cancer	Olaparib	Ⅰ	NCT05807126
	Hu5F9-G4	Solid tumors and advanced colorectal cancer	Cetuximab	Ⅰ/Ⅱ	NCT02953782
	SGN—CD47M	Advanced solid tumors		Ⅰ	NCT03957096
	IMC-002	Advanced cancer		Ⅰ	NCT05276310
	TTI-621	Hematological malignancies and solid tumor	Nivolumab, rituximab	Ⅰ	NCT02663518
	TTI-622	Relapsed/refractory multiple myeloma	Daratumumab	Ⅰ	NCT05139225
	ALX148	Gastric adenocarcinoma	Trastuzumab, ramucirumab, paclitaxel	Ⅱ/Ⅲ	NCT05002127
	ALX148	Microsatellite stable metastatic colorectal cancer	Cetuximab, pembrolizumab	Ⅱ	NCT05167409
	IBI322(anti- CD47/PD-L1 bispecific antibody)	Advanced malignant tumors lymphomas		Ⅰ	NCT04338659
	Maplirpacept	Refractory lymphoma or multiple myeloma		Ⅰ	NCT05567887
	TG-1801	B-Cell lymphoma	Ublituximab	Ⅰ	NCT03804996
	IMM2520(a PD-L1 and CD47 bispecific antibody)	Advanced solid tumors		Ⅰ	NCT05780307
SIRPα	BI 765063	Advanced solid tumors	BI 754091	Ⅰ	NCT03990233
LILRB2	JTX 8064	Advanced refractory solid tumors	Pimivalimab	Ⅰ/Ⅱ	NCT04669899
	MK-4830	Ovarian carcinoma	Pembrolizumab, paclitaxel, carboplatin	Ⅱ	NCT05446870
CD24	CD24Fc	Metastatic melanoma	Ipilimumab, nivolumab	Ⅰ/Ⅱ	NCT04060407
CCL2	Carlumab	Metastatic castrate-resistant prostate cancer		Ⅱ	NCT00992186
	CNTO 888	Solid tumors		Ⅰ	NCT00537368
CCR2	PF-04136309	Pancreatic cancer	FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, oxaliplatin	Ⅰ	NCT01413022
	64Cu-DOTA-ECLIi	Pancreatic cancer imaging		Ⅰ	NCT03851237
CXCR4	Plerixafor	Metastatic pancreatic cancer	Cemiplimab	Ⅱ	NCT04177810
	BL-8040	Metastatic pancreatic cancer	Pembrolizumab	Ⅱ	NCT02907099
CCR5	Leronlimab	Metastatic triple negative breast cancer	Carboplatin	Ⅰ/Ⅱ	NCT03838367
ANG-2/ VEGF	CVX-241	Advanced solid tumors		Ⅰ	NCT01004822
CSF-1R	BLZ945	Advanced solid tumors	PDR001	Ⅰ/Ⅱ	NCT02829723
	PLX 3397	Metastatic breast cancer	Eribulin	Ⅰ/Ⅱ	NCT01596751
	Pexidartinib	Giant cell tumor of the tendon sheath		Ⅲ	NCT02371369
	RG7155	Advanced solid tumors	Atezolizumab	Ⅰ	NCT02323191
	Cabiralizumab	Pancreatic cancer	Nivolumab, Nab-paclitaxel	Ⅱ	NCT03336216
	Cabiralizumab	Relapsed/Refractory peripheral T cell lymphoma	Nivolumab	Ⅱ	NCT03927105
Clodronate	Clodronate	Metastatic breast cancer		Ⅲ	NCT00009945
Zoledronate	Zoledronate	Renal cell carcinoma	Atorvastatin	Ⅱ	NCT00490698
CD40	APX005M	Solid tumors		Ⅰ	NCT02482168
	Mitazalimab	Advanced pancreas cancer		Ⅰ	NCT06205849
	LVGN7409	Human Papillomavirus-negative mucosal head/neck squamous cell carcinoma	PD-1inhibitor - LVGN 3616	Ⅰ	NCT06159621
	SGN-40	Multiple myeloma	Bortezomib	Ⅰ	NCT00664898
	Selicrelumab	Solid tumors	Atezolizumab	Ⅰ	NCT02304393
TLR3	Rintatolimod	Pancreatic ductal adenocarcinoma (PDAC)	Durvalumab	Ⅰ/Ⅱ	NCT05927142
	BO-112	Metastatic melanoma	Pembrolizumab	Ⅱ	NCT04570332
TLR7/8	TransCon TLR7/8 Agonist	Solid tumors	Pembrolizumab	Ⅰ/Ⅱ	NCT04799054
	TransCon (TC)	Advanced head and neck squamous Cell carcinoma	Pembrolizumab, transCon IL-2 β/γ	Ⅱ	NCT05980598
TLR9	Tilsotolimod	Advanced cancers	Ipilimumab, nivolumab	Ⅰ	NCT04270864
	CMP-001	melanoma	Nivolumab	Ⅱ	NCT03618641

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3.1. Regulation of phagocytic checkpoints

Tumor cells frequently overexpress “don't eat me” signals, which are sensed by macrophages, allowing the tumor to evade macrophage clearance [75]. Therapies targeting these signals affect the TAM phenotype, promote macrophage phagocytosis, and influence cytokine secretion [76]. Thus, regulation of the phagocytic checkpoint is of paramount importance for macrophages, given that they function as primary defenders against tumor invasion. Currently, the following phagocytic checkpoints have been investigated: the CD47/SIRPα axis; the PD-L1/PD-1 axis; the major histocompatibility complex class I (MHC-I)/leukocyte immunoglobulin-like receptor family B member 1 (LILRB1) axis; and the CD24/sialic-acid-binding Ig-like lectin 10 (Siglec-10) axis.

3.1.1. CD47/ SIRPα checkpoints

CD47, a transmembrane glycoprotein also termed integrin-associated protein, which was initially found to be expressed in red blood and healthy cells, is a key participant in the clearance of senescent cells [77]. SIRPα, a crucial inhibitory ligand of CD47, is extensively expressed on myeloid cells, including macrophages and neutrophils, and it functions to offset excessive clearance by the immune system when interacting with CD47 [78]. However, tumor cells overexpress CD47, effectively disguising themselves as healthy cells to avoid phagocytosis by macrophages [79]. Additionally, high CD47 expression on the tumor cell membrane was positively correlated with poor tumor prognosis [80]. Therefore, inhibiting the CD47/SIRPα axis facilitates the recognition of tumor cells by immune cells, thereby boosting antitumor activity. For example, fibrin gel preloaded with anti-CD47 antibodies reportedly enhances macrophage phagocytosis of cancer cells and effectively controls local tumor recurrence after surgery, thereby activating both innate and adaptive immune responses [81]. Furthermore, the RS17 peptide, derived from M1 macrophage EVs, specifically binds to CD47 on tumor cells, facilitating greater infiltration of M1 macrophages into the tumor tissue [40]. SIRPα variants are genetically engineered to overexpress on the shells of membrane-coated magnetic NPs (gCM-MNs), effectively inhibiting the CD47/SIRPα pathway. The internal core of gCM-MNs promotes the repolarization of M2 macrophages and, in combination with multiple strategies, synergistically enhances immune activation [82]. To date, numerous antagonists targeting CD47 and SIRPα have been evaluated in clinical trials, including anti-CD47 antibodies (Hu5F9-G4 (NCT02216409), SGN—CD47M (NCT03957096), IMC-002 (NCT05276310)), anti-SIRPα antibodies (BI 765063 (NCT03990233)), CD47 and SIRPα analogs (Maplirpacept (NCT05567887)), and others. ALX Oncology developed a pan-allelic anti-SIRPα antibody with a high affinity for humans, capuchin monkeys, and mice, capable of blocking the interaction with CD47 and promoting macrophage-mediated antibody-dependent immune responses without inducing hematologic toxicity [83]. In addition, the therapeutic effect of this antibody in combination with PD-1/PD-L1 blockade has been investigated, revealing that the combination promotes monocyte and dendritic cell (DC) activation while improving the effector T cell response rate [84]. Compared with nonselective SIRPα blockade, selective SIRPα blockade exhibited a synergistic effect with ICB in inhibiting tumor growth, enhancing memory T cell responses, and alleviating resistance to immunotherapy [85].

Based on the notable findings, several clinical trials and preclinical studies on macrophage CD47/SIRPα checkpoints have been initiated, as summarized in Table 2. However, the fact that CD47 is not only expressed in macrophages but is also commonly found in normal healthy cells presents a considerable challenge. Therefore, CD47 antagonists can also inhibit the function of red blood cells and platelets, resulting in the agglutination and lysis of red blood cells, ultimately leading to anemia and thrombocytopenia with severe hematotoxicity [50]. To address these issues, SIRPα antagonists, as well as antibodies with weak binding affinities, have been developed. In clinical trials, TTI-621(NCT02663518) and TTI-622(NCT05139225), which are proteins fusing the CD47-binding domain of SIRPα with the Fc structure of IgG1, appeared to minimize toxicity to red blood cells [86]. In addition, ALX148(NCT05002127), which has a specialized CD47-binding structure without an Fc activity domain, exhibited enhanced tumor-targeting ability with minimal off-target side effects [87]. However, this reduction in off-targeting effects is accompanied by a decline in the macrophage phagocytosis capacity without proper activation by Fc. Therefore, the results of these clinical trials were not favorable [88]. The above issues clearly demonstrate that, in some cases, single-antibody therapies fail to meet clinical demands. Consequently, bispecific antibody products targeting both phagocytic and tumor-specific antigens have emerged. These antibodies can promote phagocytic activity, as well as reduce off-target side effects, circumventing misleading damage to host cells that lack tumor antigen expression. Currently, antibody drugs, such as anti-CD20 (for lymphoma, NCT04599634), anti-EGFR (for colorectal cancer, NCT05167409), anti-HER2 (for breast cancer, NCT05807126), and anti-CD19 (for B-cell lymphoma, NCT03804996), as well as immune checkpoint inhibitors, such as anti-PD-L1 (NCT05780307), have been extensively investigated. Combining Hu5F9-G4, a CD47 blocker, with rituximab to treat B-cell non-Hodgkin's lymphoma markedly enhanced macrophage-mediated antibody-dependent cellular phagocytosis, resulting in notable relief of symptoms in 50% of patients, with 36% achieving complete remission [89]. Furthermore, numerous bispecific blocking antibodies have been developed. For example, IBI322, a CD47/PD-L1 bispecific antibody, targets CD47+PD-L1+ tumors and induces tumor regression [90]. Taken together, the importance of CD47 in activating adaptive immunity has been well established, and CD47/SIRPα checkpoint blockade has shown promising clinical results. However, limitations such as insufficient infiltration of solid tumors are yet to be addressed [91].

3.1.2. PD-1/PD-L1 checkpoints

PD-1 and its corresponding ligand, PD-L1, are a well-known pair of immune checkpoints. Tumors frequently overexpress PD-L1, and recognition of PD-1 on the T cell membrane induces immune tolerance, allowing the tumor to escape immune surveillance. Thus, PD-1/PD-L1 checkpoint inhibitors have been developed to treat various cancers, and several anti-PD-1 and anti-PD-L1 monoclonal antibody drugs have been approved by the US Food and Drug Administration (FDA) [92], including the PD-1 blocking agent pembrolizumab and the PD-L1 inhibitor durvalumab [93]. Monoclonal antibodies targeting glycosylated PD-L1 (gPD-L1) can effectively inhibit PD-L1/PD-1 interactions. Furthermore, drug-coupled gPD-L1 antibodies efficiently kill neighboring cancer cells that lack PD-L1 expression without inducing detectable toxicity [94]. Although commercialization of anti-PD-L1 monoclonal antibody drugs has begun, some drawbacks, such as high off-target effects and potential immune-related side effects, cannot be ignored [95]. To address these issues, Fan et al. developed an exosome-based DDS that could simultaneously incorporate several immunotherapeutic agents. This platform facilitates combination cancer immunotherapy owing to its low toxicity and high stability. Compared with the direct injection of anti-PD-L1 or anti-CD40 alone, combination application greatly improves the efficacy of immunotherapy [96,97].

Nevertheless, the PD-1/PD-L1 signaling pathway not only serves as an immune checkpoint for T cells in the traditional sense but also produces “don't eat me” signals to macrophages. This allows PD-L1⁺ tumors to evade T cell-mediated killing and phagocytosis by macrophages. TAMs express high levels of PD-1, and PD-1 expression increases in tandem with the tumor volume. Given that most PD-1+ TAMs exhibit M2-like characteristics, they can clear PD-1-blocking antibodies from T cells via FcγR, thereby weakening the efficacy [98]. Consequently, Fc-engineered IgG variants that block binding to T cells and inhibit FcγR binding were found to enhance antitumor efficacy when combined with other therapies [99]. Loading a PD-L1 antibody into a tumor-targeted nanogel facilitated antibody delivery to the tumor site, releasing it onto the surface of both tumor cells and macrophages [100]. The released antibody reactivated killer T cells and downregulated PD-L1 receptor expression on macrophages, modulating the immunosuppressive microenvironment and improving the immunotherapeutic efficacy through dual effects [101]. Collectively, the inhibition of the PD-1/PD-L1 signaling pathway can activate both innate and adaptive immunity. However, the detailed mechanism through which PD-1 inhibits phagocytosis is yet to be comprehensively clarified [102].

3.1.3. MHC-I/LILRB1 checkpoints

MHC-I is a critical component of the immune system. When MHC-I expresses abnormal protein fragments, T cells recognize and attack cancer cells [103]. However, tumor cells can evade phagocytosis by binding to members of the leukocyte immunoglobulin-like receptor (LILR) subfamily, which are widely expressed in TAMs [104]. Among the LILR subfamily members, LILRB1 is considered to be involved in phagocytosis inhibition through MHC-I regulation [105]. MHC-I expression in tumor cells is associated with resistance to anti-CD47 treatment; however, the use of LILRB1 antibodies reportedly counteracts this resistance and restores phagocytosis [104]. MHC-I also contains another ligand, LILRB2; however, its direct involvement in phagocytosis remains unclear. However, the blockade of LILRB2 effectively promoted polarization toward an anti-inflammatory phenotype and stimulated antitumor immunity [106]. JTX-8064 (NCT04669899), a LILRB2 inhibitory antibody, has been evaluated in phase 1/2 clinical trials for treating advanced malignant refractory solid tumors, both as a monotherapy and in combination with a PD-1 inhibitor. JTX-8064 relieved TAMs from their immunosuppressive condition, enhanced the antitumor efficacy of TAMs, and enhanced the function of APCs [107]. Another LILRB2 antagonist, MK-4830, in combination with pembrolizumab, showed antitumor activity in patients with advanced solid tumors. MK-4830 could be developed as a novel agent to alleviate immunotherapy resistance [108]. However, targeting the MHC-I/LILRB checkpoint still faces numerous challenges, such as the inability to broadly inhibit the growth of immune-reactive tumors and the failure to effectively treat tumors that lack or poorly express MHC-I [109].

3.1.4. CD24/Siglec-10 checkpoints

CD24 is a sialylated glycoprotein that is overexpressed in most cancer cells. It binds to the inhibitory receptor Siglec-10, which is overexpressed on TAMs and is recognized as a phagocytosis checkpoint to suppress tumor phagocytosis [110]. The expression level of CD24 was found to be associated with a poor prognosis in breast cancer and can promote tumor progression in a dose-dependent manner. Hence, CD24 is an important target for tumor therapy [111]. The application of CD24/Siglec-10 blockers reportedly restores the phagocytic properties of macrophages and blocks tumor growth [112]. Moreover, the administration of exogenous Siglec-10 engineered with EVs derived from 4T1 cells blocked the interaction between CD24 on cancer cells and Siglec-10 on macrophages. This approach could synergistically stimulate the transition of M2 to M1 macrophages through ROS generated by photodynamic therapy, thereby activating tumor immunity [113]. Combining a Siglec-10 competitive binding antibody with pembrolizumab enhanced the cytotoxicity of CD8⁺ T cells against hepatocellular carcinoma, resulting in improved antitumor effects [114].

3.1.5. Other checkpoints

In addition to the aforementioned “don't eat me” signals, several other checkpoint pathways are worth exploring, including stanniocalcin 1 (STC-1), glycosylated disialoganglioside 2 (GD2), and CD22. Among them, STC-1 acts as an inhibitor of “eat me” signaling by capturing calreticulin and blocking its specific phagocytosis by macrophages. This plays an important role in tumor escape and immune resistance [115]. Another phagocytic checkpoint molecule is GD2, which specifically binds to Siglec-7. Anti-GD2 and anti-CD47 antibodies have been shown to work synergistically to promote macrophage-mediated phagocytosis [116]. Moreover, CD22, which is specifically expressed in B cells, has been identified as a phagocytic inhibitor of microglia. However, the specific mechanisms underlying their role in phagocytosis require further investigation [117].

In summary, with the growing number of phagocytic checkpoints under investigation, research on “don't eat me” signaling has advanced rapidly. Currently, most clinical trials targeting macrophage phagocytic checkpoints are either active or complete (Table 2). Although preliminary outcomes for drugs targeting the CD47/SIRPα and PD-1/PD-L1 axis have been reported, several possible risks associated with the use of phagocytic checkpoint inhibitors need to be addressed. Notably, phagocytic checkpoints function through innate ligand-receptor interactions, which have low specificity and may damage normal tissues. Consequently, phagocytic checkpoint inhibition is frequently combined with ICB or other immunotherapies to enhance tumor targeting and reduce off-target effects.

3.2. Inhibition of macrophage recruitment

Chemokines present in the TME and their interactions with their corresponding ligands play prominent roles in the recruitment and regulation of TAMs [118]. Therefore, targeting chemokines to inhibit TAM recruitment has emerged as a key strategy to modulate the immunosuppressive microenvironment. TAMs originate from CCR2+ precursor monocytes, which are specifically recruited to the TME by CCL2 secreted by tumor cells [119,120]. The use of small-molecule inhibitors such as zoledronic acid or antibodies targeting CCR2 can block the release of CCL2 into the TME, leading to the inhibition of TAM recruitment and infiltration with enhanced antitumor immune responses. For example, cationic polymeric NPs encapsulating siCCR2 (CNP/siCCR2) showed remarkable targeting of monocytes, effectively altered the immunosuppressive TME, and exhibited superior antitumor effects in a breast cancer model [121]. By blocking the CCL2/CCR2 signaling axis, this approach suppressed the recruitment of inflammatory monocytes, decreased breast cancer metastasis, and increased the survival time of tumor-bearing mice [122]. Copper NPs (Cu@CuO_x) targeting CCR2 not only selectively target tumors for emission tomography imaging but also deliver chemotherapeutic agents directly to tumor sites. This dual functionality reduces the toxicity and side effects of chemotherapy while achieving excellent therapeutic efficacy [123].

Additionally, carlumab (an anti-CCL2), a single agent for the treatment of metastatic castrate-resistant prostate cancer, has completed a phase 2 clinical trial (NCT00992186) [124] and is being evaluated in combination with chemotherapy for other solid tumors (NCT00537368). Conversely, activation of CCL2 secretion promotes the release of suppressive monocytes into the TME, contributing to angiogenesis and lung metastasis in an IL-6- and VEGF-A-dependent manner [125]. Notably, other chemokines, such as CCL5/CCR5 and CXCL12/CXCR4, are also involved in recruitment, thereby contributing to tumor recurrence. For instance, maraviroc, an FDA-approved CCR5 inhibitor for HIV treatment, is currently being investigated in clinical trials for various types of tumors, including advanced colorectal cancer with liver metastases (NCT01736813), with no significant side effects reported. Furthermore, verteporfin, a CCL5/CCR5 antagonist more potent than the conventional antagonist maraviroc, substantially inhibited the growth of triple-negative breast cancer tumors and exerted a critical function in metastasis by regulating epithelial-mesenchymal transition transcription factors [126]. A phase 2 clinical trial of plerixafor, a CXCR4 antagonist, in combination with cemiplimab, has been completed to treat metastatic pancreatic cancer (NCT04177810). The results revealed that blocking CXCL12 (SDF-1)/CXCR4 signaling reduced pancreatic cancer cell migration and invasion in vitro, highlighting its potential as a promising target for preventing pancreatic cancer progression [127].

TAMs are also involved in angiogenesis, secreting VEGF, and are regulated by various vascular growth factors [128]. In combination with M2 peptide-based targeted immunotherapy, RNA interference NPs containing anti-VEGF reduced the recruitment of inflammatory TAMs and suppressed tumor growth [129]. However, aberrant expression of angiopoietin-2 (Ang-2) impairs vascular normalization and interferes with anti-VEGF therapy, leading to evasion resistance. Therefore, the dual inhibition of VEGF and Ang-2 signaling has been explored in immunotherapy for glioblastoma (GBM). The results showed effective tumor growth reduction, enhanced tumorigenic necrosis, inhibition of TAM recruitment, and normalization of vascular morphology [130], offering a promising strategy to overcome the limitations of anti-VEGF monotherapy in GBM.

3.3. Depletion of TAMs

Depletion of M2-type macrophages while retaining M1-type macrophages with antitumor functions is an emerging strategy for directly targeting suppressive immune cells. CD163, a classical M2 macrophage marker, is strongly associated with tumor proliferation, metastasis, and drug resistance [131]. Reportedly, specific depletion of CD163⁺ macrophages promotes the infiltration of activated T cells and induces tumor regression [132].

Another important strategy for TAM depletion is the specific blockade of CSF1/CSF1R (CSF1 receptor) signaling, which prevents tumor-promoting activation. CSF1 is an important cytokine that induces macrophage polarization to the M2 phenotype, and it has been shown that targeting macrophages by blocking CSF1R effectively inhibits tumor growth and metastasis. Anti-CSF1R siRNA, when loaded into bispecific NPs (M2NPs) equipped with M2-pep and scavenger receptor B1(SR-B1)-targeting peptides, blocks the survival signals of M2-like TAMs, promotes CD8⁺ T cell infiltration, and enhances IFN-γ secretion [133]. Currently, CSF1/CSF1R targeting drugs, including BLZ945 (NCT02829723), PLX3397 (NCT01596751; NCT02371369), RG7155 (NCT02323191), and cabiralizumab (NCT03336216; NCT03927105), under investigation in clinical trials. For example, the CSF1R inhibitor BLZ945, encapsulated in NPs, was found to deplete CD163⁺ TAM and inhibit neuroblastoma growth [134]. Another approach involves encapsulating BLZ945 in pH-responsive micelles coated with erythrocyte-cancer cell hybrid membranes. In an acidic TME, these micelles efficiently bind to the CD206 receptor, allowing them to be recognized and internalized by TAMs, thereby promoting TAM depletion [135]. Another CSF1R inhibitor, PLX3397, has been approved by the FDA to treat tenosynovial giant cell tumors [136]. Treatment with PLX3397 depleted TAMs and FOXP3+ regulatory T cells and enhanced CD8⁺ T cell infiltration. This notable modulation of both macrophages and T cells suggests that PLX3397 is a promising immunotherapy strategy [137]. Despite their documented promise in inhibiting tumor growth and modulating the immune microenvironment, these drugs also have limitations. T cell-induced enrichment is closely related to CD8⁺ T cell-dependent PD-1 blockade resistance mechanisms [138]. However, the CSF1/CSF1R blockade alone is often ineffective. Therefore, CSF1/CSFR1 blockade is typically combined with checkpoint blockade or other T cell-based immunotherapies to achieve better therapeutic effects. Nevertheless, CSF1R blockade can induce adverse events, given that macrophages play critical roles in innate immunity, hematopoietic microenvironment homeostasis, embryonic tissue development, and tissue repair [17]. Taken together, the clinical application of CSF1/CSFR1 blocking drugs warrants further investigation.

In addition to the above-discussed blockers, bisphosphonate chemotherapy drugs, such as clodronate and zoledronate, exhibit direct antitumor efficacy by inducing cancer cell apoptosis and blocking angiogenesis while indirectly promoting tumor elimination by depleting TAMs [139]. However, given the low bioavailability and high cytotoxicity of these agents, bisphosphonate-loaded liposomes have been widely developed to improve their efficacy and reduce toxicity [140]. Zoledronic acid and IR780, a hydrophobic photosensitizer, were co-encapsulated within liposomes, designed to degrade in response to H₂O₂ in the TME, releasing the encapsulated agents. The released Zol binds to microcalcifications and is selectively phagocytosed by TAMs, inducing death or repolarization of TAMs from an immunosuppressive M2 phenotype and cooperating with photodynamic immunotherapy to inhibit breast cancer [141]. Moreover, Rodriguez-Garcia et al. employed CAR-T cells targeting folate receptor-β (FRβ) to selectively eliminate FRβ+ immunosuppressive TAMs in the TME, enhancing the infiltration of endogenous tumor-specific CD8⁺ T cells and prolonging survival [142].

Nevertheless, the TME is a highly dynamic and complex system, and the depletion of M2-type macrophages does not necessarily result in a stronger antitumor response by the remaining M1-type macrophages. This process is not straightforward, and the status of multiple components within the TME must be considered [143]. For instance, following the depletion of M2-type macrophages, the tumor may adapt by activating other immune escape mechanisms, such as recruiting regulatory T cells (Tregs) or MDSCs, to compensate for the loss of M2 macrophages [144]. Furthermore, the limited number of M1-type macrophages may be insufficient for complete tumor eradication. Despite their high activity, the remaining M1 macrophages may lack the persistence required to sustain a long-term antitumor immune response, especially in an immunosuppressive TME [15]. In summary, while residual M1-type macrophages may exert antitumor effects following M2 depletion, their ability to effectively suppress tumor growth depends on multiple factors, including the immunosuppressive nature of the TME, the function and quantity of M1 macrophages, and the capacity of the tumor to adapt to immune surveillance. Thus, M2-type macrophage depletion alone is often inadequate to fully inhibit tumor growth and should be combined with other immunotherapies for enhanced efficacy.

3.4. Reprograming TAMs

Although the depletion of TAMs and inhibition of their recruitment are effective strategies, the pivotal role of M1 macrophages in the TME cannot be disregarded. Reprogramming M2 macrophages to adopt an antitumor M1 phenotype represents a crucial approach for converting “cold” tumors into “hot” ones. However, the selective targeting of M2 macrophages using conventional drugs remains challenging. Therefore, combining M2-targeting peptides, such as M2-pep, with cytokines, immune agonists, or inhibitors is commonly employed to reprogram TAMs. To achieve high localized concentrations of IL-12, pro-inflammatory vectors overexpressing IL-12 were constructed through genetic modifications. This vector effectively reprogrammed macrophages and recruited DCs, thereby activating CD8⁺ T cells and eliciting robust antitumor responses [145]. CD40, a cell surface member of the TNF receptor family expressed on APCs, and its ligand CD40L form a highly conserved costimulatory molecule pair. Their binding results in the production of TNF and ROS, which permit a series of APCs, such as macrophages, to activate T cells and re-educate killer T cells to target and destroy tumors [50]. The activation of CD40 not only enhances the efficacy of anti-PD-L1 therapy but also sensitizes immune checkpoints [146]. Moreover, it effectively enhances the therapeutic outcomes of first-line chemotherapy regimens, such as gemcitabine and cisplatin, while concurrently reducing tumor burden [147]. Additionally, the combined blockade of CSF1R and activation of CD40 effectively modulated suppressive myeloid cells within the TME, promoting a shift toward an inflammatory milieu. This leads to the enhanced maturation and differentiation of pro-inflammatory macrophages and initiates effector T cell-mediated cytotoxicity [148].

Toll-like receptor (TLR) agonists have also been shown to reprogram TAM and activate innate and adaptive immune responses. The TLR3 agonist poly (I:C), complexed with arginine-rich polypeptides and encapsulated in an anionic polymeric layer, effectively mitigated systemic toxicity. This approach simultaneously promoted T cell recruitment and induced the secretion of the chemokines CXCL10 and CCL5, resulting in the direct elimination of cancer cells by cytotoxic M1-polarized macrophages [149]. Combined use of rintatolimod, a TLR-3 agonist, and durvalumab, a PD-L1 inhibitor, is under investigation to treat metastatic pancreatic ductal adenocarcinoma (NCT05927142). Another TLR7/8 agonist encapsulated in a radiosensitive peptide hydrogel (Smac-TLR7/8 hydrogel) has been used as an adjuvant for radiotherapy and was found to induce TAM repolarization and enhance TNF secretion, thereby augmenting the immunogenic phenotype of the tumor by increasing the number of tumor-infiltrating lymphocytes and decreasing the number of Treg cells. Consequently, it enhances the efficacy of PD-1 blockade and plays a crucial role in overcoming resistance to radiotherapy and immunotherapy [150].

Recently, in vitro-transcribed mRNAs have been suggested as a potential new drug category for inducing cellular reprogramming. In mouse models of ovarian cancer, melanoma, and GBM, the infusion of NPs formulated with mRNA encoding interferon regulatory factor 5 (IRF5) and its activating kinase IKKβ, in combination with an inhibitor of the NF-κB kinase subunit β (IKKβ), effectively reversed immunosuppressive TAMs. This reprogrammed them into a phenotype that induces antitumor immunity, leading to tumor regression without causing systemic toxicity [151]. In addition, treatment with lipid-based NPs and CD24-Siglec-G blockers, which produce CAR-Ms, substantially enhanced phagocytosis of hepatic macrophages in a mouse model of hepatocellular carcinoma, resulting in a remarkedly high survival rate [152]. Importantly, TAM reprogramming was shown to be tightly linked to microRNAs (miRNAs), which have emerged as key regulators of macrophage differentiation and polarization, including TAMs [118,153]. miRNA-based therapies have been evaluated in various experimental tumor models. Targeting and reprogramming of TAMs using miRNAs has emerged as a promising therapeutic strategy for tumor immunotherapy. For instance, the delivery of miRNA-155 to TAMs has been achieved using lipid-based calcium phosphonate NPs. The incorporation of pH-sensitive materials enables their release into the acidic TME, thereby effectively reprogramming TAMs into antitumor macrophages [154]. Additionally, the reprogramming can be regulated by inhibiting specific miRNAs. For example, exosomes loaded with 5-fluorouracil (5-FU) and a miR-21 inhibitor (miR-21i) demonstrated notable antitumor effects. Interestingly, in a mouse model of colon cancer, the co-delivery of 5-FU and miR-21i using engineered exosomes efficiently reversed monotherapy resistance and improved cytotoxicity in 5-FU-resistant colon cancer cells [155].

Hypoxia is a distinctive feature of solid tumors that promotes tumor aggressiveness and leads to the accumulation of TAM with an immunosuppressive phenotype. Consequently, various MnO₂ NPs are continuously being developed owing to their potential to alleviate hypoxia [156]. For instance, synergistic therapy with MnO₂ NPs and the anti-angiogenic drug sorafenib not only modulated the hypoxic TME and catalyzed endogenous H₂O₂ decomposition to produce oxygen but also regulated TAM polarization and promoted macrophage proliferation with an immunostimulatory M1 phenotype. Simultaneously, sorafenib reduced tumorigenic vasculature and synergistically overcame hypoxia-induced drug resistance, thereby enhancing the immunotherapeutic efficacy of anti-PD-1 antibodies [157]. Song et al. employed MnO₂ NPs to modulate the oxygen concentration and pH within the TME, utilizing TAMs for targeted accumulation in hypoxic regions to reprogram M2-type macrophages, achieving enhanced modulation of chemotherapeutic resistance and inhibition of tumor cell proliferation [158]. In addition to the aforementioned factors, excessive matrix stiffness resulting from collagen overdeposition and crosslinking serves as a further physical factor that regulates macrophage polarization [159]. M2-type TAMs promote matrix deposition and modulate MMPs to remodel the extracellular matrix (ECM) [160]. To address this pathological cascade, an ECM nanoremodeler (SPNcb) was engineered to integrate TME-activated inhibition of collagen-crosslinking enzymes with photodynamic therapy. This synergistic strategy effectively reduced ECM stiffness, modulated tumor immune infiltration, and ultimately suppressed tumor progression through the combined regulation of biomechanical and photodynamic microenvironments [161].

4. Engineered macrophages as DDSs

Owing to their inherent homing properties, macrophages can actively migrate toward inflamed and injured tissues, guided by various chemokines, allowing them to selectively accumulate at tumor sites. Based on this characteristic, macrophages are superior candidates for cell-mediated biomimetic DDSs compared to traditional exogenous DDSs such as liposomes and NPs, as well as other endogenous cell-based DDSs, including those derived from red blood cells, neutrophils, and dendritic cells [162]. Table 3 presents a detailed comparison of the advantages and disadvantages of macrophage-based DDSs with those of other types of DDSs. Macrophage-based DDSs not only extend the circulation time of drugs in the bloodstream and exhibit excellent biocompatibility but also possess phagocytic capabilities, allowing them to defend against host attacks and internalize large quantities of drugs for precise delivery to tumor sites. Additionally, macrophage-based DDSs actively participate in immune modulation and promote the formation of M1-type TAMs. They also function as antigen-presenting components, facilitating T cell activation to promote antitumor immune responses [163]. Therefore, in this section, we explore various strategies for macrophage-based drug delivery, including the use of live macrophages as carriers for drug delivery (Fig. 5), the incorporation of drugs within macrophage membrane-mediated biomimetic nanocarriers (Fig. 6), and the development of CAR-M constructs (Fig. 7).

Table 3.

Advantages and limitation of different types DDSs for cancer immunotherapy.

DDS	Advantages	Limitation
Erythrocyte-mediated DDS	Long survival period for long drug release; Natural biocompatibility and biodegradability; Low immunogenicity.	Requiring a large amount of source materials; Lack of proper storage methods; High risk of immunological rejection.
Macrophage-mediated DDS	Phagocytic ability to internalize drugs in large quantities; Long circulation of drugs in the bloodstream; Inherent tumor homing capability; Participating in immune modulation and contributing to anti-tumor immunity.	Heterogeneity of macrophages may lead to unequal drug distribution; Uncontrolled release of drugs.
Neutrophil-mediated DDS	Good tissue penetration capability; Good biodegradability.	Short life span; Difficulty in mass cultivation; Primarily focused on the early stages of inflammation, with limited ability to target the TME.
DC-mediated DDS	Strong antigen presentation ability to effectively activate the immune response; Available for vaccine development.	Low maturing efficiency; Complex in vitro manipulation required; Sensitive to cell state and susceptible to external factors.
NK cell-mediated DDS	Killing target cells without pre-recognition of antigens; Release cytokines and chemokines; Available for acute viral infections and cancer treatment.	Shorter survival time in the body; Low expansion and activation; Difficulty in mass cultivation; Activity susceptible to inhibitors.
T cell-mediated DDS	Highly specific to directly identify and kill tumor cells; Memory effect with long-term protection; Low immunogenicity.	Complex preparation and expansion processes; Triggering auto-immune reactions; High cytokine release syndrome; High cost.
Conventional DDS	Simple preparations; Low cost; Easy surface modification for improved targeting; Capability to encapsulate water-soluble and lipid-soluble drugs.	Poor stability and prone to leakage; Limited drug loading capacity; Poor biocompatibility; Risk of side effects.

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Fig 5 — Diverse drug loading strategies employed by viable macrophages as carriers for drug delivery. (A) Direct incubation with chemotherapeutic agents; (B) Internalization of NPs; (C) Ligand–receptor attachment; (D) Covalent coupling; (E) Other genetic modification processes, such as macrophages knocked out of SIRP-α gene by the CRISPR-Cas9 gene editing mechanism; (F) Delivery of oncolytic virus (OV).

Fig 6 — Schemes of macrophage membrane-mediated biomimetic nanocarriers. (A) Synthetic NPs derived from macrophages. They are assembled by synthesized phospholipid bilayers together with extracted membrane proteins or macrophage membranes; (B) Synthesis of NPs encapsulated in macrophage membranes.

Fig 7 — Illustration of the CAR-M architecture and its benefits in the treatment of solid tumors.

4.1. Live macrophages as a therapeutic strategy

Macrophages can serve as living cell carriers for loading drugs or therapeutic molecules within their interiors or onto their surfaces. Once macrophages reach the tumor site, the drugs are released, ensuring sufficient drug concentration at the target location. Initially, direct incubation was considered the simplest approach for internalizing chemotherapeutic agents into macrophages (Fig. 5A) [164]. M1 macrophages were selected as delivery vehicles because of their inherent antitumor properties, and doxorubicin (DOX) loading further enhanced tumor tropism by upregulating CCR2 and CCR4 expression. Furthermore, DOX-loaded M1 macrophages (M1-DOX) infiltrated deep into tumor lesions, leading to prolonged overall survival in a peritoneal metastatic ovarian carcinoma model [165]. However, this strategy presents challenges: chemotherapeutic drugs not only affect macrophage homing efficiency but also limit the loading capacity. Therefore, NP DDSs have been explored as an alternative to free drug loading.

Macrophage carriers loaded with NPs exhibited lower off-target toxicity than those loaded with free chemotherapeutic drugs (Fig. 5B) [166]. For instance, nanospheres (CpG-ASO-Pt) (CAP), comprising a nucleic acid therapeutic agent (CpG-ASO) and the chemotherapeutic drug cisplatin (Pt), were loaded into the RAW 264.7 macrophage-based drug delivery platform (CAP@M). This approach maintained immune stimulation, as well as enhanced the killing efficacy of macrophages against non-small cell lung cancer [167]. Macrophages bearing responsive NPs are frequently used to control drug loading and release. This involves triggering drug release by altering external factors such as pH, temperature, light exposure, or ultrasound stimulation [168]. A macrophage-based temperature-sensitive nanotherapeutic, DDS (AuNRs+ DOX-LPs@RAW), fully exploited the synergistic effect of chemotherapy and photothermal therapy (PTT) through phagocytosis of the anticancer drug DOX liposomes and gold nanorods. The use of macrophages for encapsulation markedly enhanced tumor penetration and coverage of NPs [169]. Furthermore, Das et al. developed bioorthogonal nanozymes (NEs) that remained active for 72 h after phagocytosis by macrophages when embedded in self-assembled gold NP (AuNPs) along with transition metal catalysts (TMCs). NEs effectively dissolved and stabilized TMCs, thereby controlling drug release and preserving the active targeting ability of macrophages toward tumors [170].

In addition to the aforementioned strategies for loading chemotherapeutic drugs and NPs in vitro, NPs of appropriate sizes and/or modifications can be directly injected in vivo, where they are taken up by resident macrophages or TAMs, which subsequently transport the drug to the tumor site for sustained release [171]. Specific binding of ligands on liposomes to macrophage surface receptors in vivo is crucial for efficient drug internalization. For example, oligomannose-coated liposomes undergo internalization by macrophages following intraperitoneal injection and accumulate at the site of tumor metastasis [172]. Additionally, sialic acid-modified liposomes facilitate drug delivery by recognizing the Siglec-1 receptors on TAMs. Sialic acid receptor-mediated targeting of TAMs elicits robust cellular uptake and greater cytotoxicity in tumors [173]. Subsequently, liposomes co-loaded with chlorogenic acid and DOX stimulate the conversion of M2-type TAMs to M1-type and directly kill melanoma cells, thereby enhancing therapeutic efficacy [174]. Although both these approaches can substantially extend the circulation half-life of drugs, the implementation of a macrophage-internalized NP strategy faces numerous limitations: (1) susceptibility to macrophage apoptosis and dysfunction owing to low bioavailability at high concentrations of exogenous synthetic NPs, while sublethal amounts may result in therapeutic failure owing to insufficient loading doses; (2) difficulty in preparing macrophage-based DDSs that can encapsulate responsive NPs; (3) trapping of drugs by phagosomes and difficulty in release; and (4) premature drug release or degradation within macrophages, which may compromise therapeutic efficacy.

To address challenges related to macrophage-based DDSs and prevent drug degradation, different strategies have been developed to increase the stability and targeting precision of drugs. These strategies primarily include drug-conjugated ligand-receptor attachment, covalent coupling, and gene-knockout approaches for modifying macrophages. Ligand-drug conjugates exhibit antitumor activity by binding their Fc domains to cancer-associated membrane receptors. This binding ensures both the stability of the drug and its precise delivery to tumor sites, thereby enhancing therapeutic efficacy while minimizing off-target toxicity (Fig. 5C) [175]. For example, to enhance the specificity of HER2+ tumor cell targeting, anti-HER2 affibodies APC TLR were genetically engineered to the macrophage membrane surface (AE-Mφ), enabling the highly selective accumulation of engineered macrophages at the tumor site and efficient blockade of intracellular HER2 signaling pathway, which enhanced antitumor efficacy [176]. However, ligand-receptor attachment remains insufficient in most cases, which can be attributed to the inadequate binding affinity to sustain localization at the target site. Additionally, nonspecific conjugation with untargeted cells can compromise delivery efficiency. Covalent coupling can markedly resolve these issues by leveraging the stronger binding of covalent bonds, thereby avoiding potential receptor activation and enabling more precise targeting of the tumor region to prevent nonspecific binding (Fig. 5D) [177]. Aptamer-engineered M1 macrophages (ApEn-M1), generated using azido-alkenyl group click chemistry and anchored with AS1411 and PD-L1 aptamers, exhibit specific recognition of nucleolin on the cancer cell surface while simultaneously binding to PD-L1, resulting in the inhibition of immune checkpoints and promotion of tumor eradication [178]. Moreover, following treatment with reducing agents, the NPs stably bonded to the macrophage surface through secondary amine linkages, thereby providing several new sites for anticancer drug loading. This configuration minimizes the toxic effects of drugs on the carrier cell viability and reduces off-target effects [179]. In addition to these strategies, other genetic modification approaches have been employed (Fig. 5E). For instance, transplantation of hematopoietic progenitors with the Tie2 promoter/enhancer-driven IFNA1 gene induces the substantial production of IFN-α, leading to notable antitumor responses and inhibition of tumor angiogenesis [180]. Additionally, macrophages with SIRP-α knockout via the CRISPR-Cas9 gene editing method exhibited a four-fold enhancement in their intrinsic phagocytic capacity because they no longer received the inhibitory “don't eat me” signal from cancer cells [181]. In addition to the aforementioned NPs, macrophages have been shown to internalize oncolytic adenoviruses. When guided by magnetically sensitive NPs, macrophages carrying oncolytic adenoviruses could effectively infiltrate the primary tumor site, resulting in reduced tumor burden and metastasis (Fig. 5F) [182].

Accordingly, engineered macrophage-mediated cellular therapy represents a nascent field in DDSs. However, inherent challenges associated with the application of living cells as DDSs need to be addressed. Numerous innovative delivery strategies have emerged, and several well-established strategies are listed in Table 4. The subsequent effects of macrophage modifications on their activity and delivery efficiency require warrant investigation, particularly with regard to cargo loading, drug properties, and loading methods.

Table 4.

Advantages and disadvantages of different approaches for loading drugs in live macrophage DDS.

Drug loading strategies		Advantages	Disadvantages	Ref.
Direct incubation with chemotherapeutic agents		Simple operation; No specialized equipment required.	Impair cell viability, limited macrophage homing efficiency, and low loading capacity.	[164,165]
Internalization of NPs		Low cytotoxicity; High drug loading rate; Simple operation.	Releasing drugs prematurely or drug degradation; phagosome engulfment of drugs leading to hindered release; impeding macrophage function; Difficulty in preparation.	[[167], [168], [169], [170],257]
Genetically engineered modified macrophages	Ligand–receptor attachment	Reproducible connections; Specifical ligand-receptor binding can be accomplished in vivo; Simple purification of target cells.	Binding affinity is insufficient to sustain the target site; Non-specific attachment with certain undesired cells; Trigger some unneeded biological responses.	[175,176]
	Covalent coupling	Covalent bonds provide strong coupling to avoid triggering receptor activation; More precise targeting.	Difficult to separate the drug from the carriers; More complicated purification operations.	[[177], [178], [179]]
	Other genetic modification processes	Greater focus on specific tumors; Customized treatments for precision medicine.	Difficult operations; Higher failure risk; Limited applicability pose challenges.	[180,181]
Delivery of OV		High concentration of progeny viruses in a short time; Strong tumor killing effect; Wide tissue tropism; Less susceptible to drug resistance.	Releasing drugs prematurely or drug degradation; phagosome engulfment of drugs leading to hindered release; impeding macrophage function; Excessive activation of the immune response.	[182,258,259]

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4.2. Macrophage membrane-derived biomimetic nanocarriers

Living cells face considerable obstacles in delivering drugs in vivo, as ensuring that macrophages remain sufficiently active to effectively deliver drugs to tumor sites can be challenging. To address this issue, researchers have pioneered cell membrane coating technology. Because macrophages have abundant surface receptors and innate tropism for tumors, natural macrophage membranes or membrane surface proteins can be employed to package NPs to achieve macrophage membrane-functionalized nanosystems that harness the benefits of both macrophages and nano-delivery systems. As shown in Fig. 6, this section focuses on reviewing macrophage membrane-derived biomimetic nanosystems, including synthetic NPs derived from macrophages and NPs encapsulated in macrophage membranes.

4.2.1. Synthetic NPs derived from macrophages

The active targeting of tumors by macrophage membrane surface-specific proteins is a key factor in constructing macrophage-based DDSs. The extraction and binding of essential membrane proteins from macrophages to synthesize liposomes is a straightforward approach for creating biomimetic NPs with properties similar to those of live macrophages (Fig. 6A) [183]. Using this strategy, antitumor drugs have been successfully delivered to the tumor vascular system by modifying key membrane proteins on the surface of NPs that specifically bind to cell adhesion molecules, such as LFA-1, Mac-1 and PSGL-1. Compared with free chemotherapeutic drugs, these macrophage membrane protein-modified drugs exhibited enhanced tumor accumulation and prolonged survival in melanoma and breast cancer models. Additionally, macrophage membrane protein-modified DDSs demonstrated superior targeting capabilities with reduced clearance to conventional liposomal formulations [184].

Accordingly, biomimetic hybrid liposomes have been developed by incorporating synthetic NPs into extracted cell membranes, enabling the fusion of various types of NPs with different cell membranes for diverse modification purposes. A multifunctional drug delivery platform has been formulated by fusing platinum NPs (nano-Pt) with vesicles comprising mouse RAW 264.7 cell membranes via freezing and extrusion. The incorporation of nano-Pt into the fusion vesicles conferred active tumor targeting, enhanced immune escape resistance, and improved tumor eradication [185]. Additionally, paclitaxel liposomes were found to co-fuse with the plasma membrane components of both macrophages (mouse J774A.1 cells) and tumor cells (head and neck tumor cells HN12). The introduction of exogenous phospholipids furnished superior drug-carrying properties while promoting supracellular membrane-targeted tumor-specific immune escape. This approach can prolong the drug circulation time in the bloodstream and markedly block tumor growth [186]. Overall, both aforementioned strategies successfully modified exogenous NPs into biomimetic NPs, improving their biocompatibility while enhancing targeting to the tumor interior.

4.2.2. NPs encapsulated with macrophage membranes

Although the aforementioned strategy has substantial potential, a growing number of studies have focused on utilizing macrophage membrane-encapsulated NPs as drug delivery carriers. In this context, NPs are packaged with macrophage membranes using cell membrane coating technology and used as “ghost” macrophages [187]. This approach primarily relies on specific receptors or adhesion factors on the macrophage membrane, such as CCR2/CCL2 [122], α4 and β1 integrins/VCAM-1 [188], and LFA-1/ICAM-1 [21], recognizing and interacting with tumor cells. Furthermore, functional membrane proteins, including CD45, CD11a and glycans, function as protective shields for encapsulated NPs against phagocytes or uptake by endothelial cells in the circulation, thereby facilitating successful targeting of NPs to tumor cells [189]. For example, a biomimetic nano-delivery system [(C/I)BP@B-A(D)&M1m] constructed using M1 macrophage membrane-encapsulated NPs was found to delay phagocytosis clearance and exhibited better tumor targeting than non-polarized macrophage membrane (M0m)s. DOX-loaded small NPs [B-A(D)] can effectively penetrate deep into the tumor and continuously release DOX to induce tumor immune cell death. It not only suppressed primary tumor growth but also prevented tumor recurrence and metastasis [190]. TAMM can also be used to encapsulate NPs and plays a unique role in the TME owing to its unique antigen-homing affinity and superior immunocompatibility. For example, TAMM-coated NPs can deplete CSF1 produced by cancer cells in the TME, thereby blocking the interaction between TAM and cancer cells and effectively depleting TAM. A TAM-like upconversion nanoprocessor phosphatidylserine (NPR@TAMM) was constructed using TAMM. NPR@TAMM-mediated photodynamic immunotherapy reprogrammed macrophages from an immunosuppressive M2-like phenotype to an M1-like phenotype, triggered immunogenic cell death, and exhibited superior antitumor immune effects [22,191]. TAMM-encapsulated NPs containing self-amplifying ROS-sensitive precursors could effectively scavenge CSF1 secreted by tumor cells and target tumors and lung metastatic nodules, resulting in effective chemo-sensitizing immunotherapy [192]. Moreover, the cell membrane for coating may not only be derived from a single cell type but can also be formed by fusing membranes from multiple cells to create a hybrid membrane coating. For instance, the fusion of macrophage membranes to cancer cell membranes is frequently employed to specifically target homotypic tumor cells and effectively eliminate lung metastasis. DOX-loaded NPs encapsulated with hybrid membranes comprising RAW264.7 and breast cancer 4T1 cell membranes demonstrated a markedly enhanced ability to combat breast cancer lung metastasis, achieving an impressive anti-metastatic efficacy of approximately 88.9% [193].

The preparation of macrophage-encapsulating NPs involves three essential steps: (1) extraction of cell membranes from source cells, (2) preparation of NP cores, and (3) fusion of membranes with NPs [194]. Among these steps, cell membrane extraction primarily includes cell lysis and purification using a hypotonic solution or repeated freezing and thawing to fragment the cell membranes [195]. Subsequently, the soluble proteins were removed by repeated ultracentrifugation, resulting in homogenized vesicles obtained via extrusion or sonication. Alternatively, other methods have been employed for macrophage membrane extraction, including freeze-drying-thawing in liquid nitrogen and multiple rounds of buffer washing [196]. The subsequent step involves the fabrication of core NPs using efficacious drugs. Over the past few years, a wide range of NPs has been developed, primarily composed of organic polymers and inorganic materials. Organic polymeric materials include PLGA, albumin, chitosan, and gelatin [197]. PLGA NPs are one of the most prevalent FDA-approved NP types because of their excellent biocompatibility and ability to effectively mitigate drug cytotoxicity [198]. Alternatively, core NPs can be fabricated using inorganic materials, such as mesoporous silica nanocapsules (MSN) [199], iron oxide NPs [200] or gold NPs [201], which exert biological effects through physical factors such as light, electricity, temperature and magnetism.

The fusion of separately harvested cell membranes and core NPs has furnished novel biomimetic NPs. Several cell coating techniques have been proposed, including extrusion, sonication, electroporation, and in situ production [202]. The advantages and disadvantages of these fusion methods are summarized in Table 5. Currently, membrane extrusion and sonication are the two most widely used methods [203]. During membrane extrusion, cell membranes are mixed with NPs and extruded through polycarbonate membranes with varying pore sizes, allowing NP encapsulation within the membranes through mechanical forces. The M1-type macrophage membrane-encapsulated SN38 polymer-conjugated camptothecin prodrug NPs were prepared using the extrusion method. These NPs showed enhanced tumor accumulation and notable tumor growth inhibition compared with conventional NPs [204]. Moreover, the 1, 2-distearoyl-sn‑glycero‑3-phosphoethanolamine-PEG plasma membrane camouflaged with macrophage membranes could cross the blood-brain barrier (BBB), enabling the delivery of synthesized MDINP (macrophage membrane-derived NP) fluorescent probes to GBM tumor cell sites for GBMPTT-induced growth inhibition [205]. Despite the controlled size of produced NPs, this approach faces inefficiencies, challenges in scaling up production, and potential disruption of cell membrane integrity. Sonication fusion is an alternative method that offers reduced loss and enhanced operational convenience. However, optimizing sonication conditions is necessary to enhance the fusion efficiency [206]. Macrophage membrane-coated rapamycin-loaded NPs (MRaNPs) were developed to specifically downregulate the mTOR pathway via genetic targeting of macrophages, thereby effectively inhibiting angiogenesis [207]. Recently, electroporation, including microfluidic electroporation, has emerged as a high-throughput and efficient drug delivery technique [[208], [209], [210]]. This method uses electrical pulses to induce transient pores in the cell membrane within an electric field, thereby facilitating NP entry while maintaining membrane integrity and stability [211]. Microfluidics operates on the same principle by introducing the membrane and core NPs through separate channels, which are then mixed and fused via electroporation to generate highly efficient and reliable NPs [212]. However, transient actions require more demanding conditions. Oversized particles cannot be loaded, and the parameters of the conditions must be optimized. Additionally, an alternative fusion strategy involves NP internalization by viable macrophages, followed by their activation through electroporation-induced membrane permeabilization, resulting in the release of intracellular contents and formation of endogenous macrophage vesicles encapsulating exogenous NPs while preserving intact cellular membranes for enhanced biocompatibility [213].

Table 5.

Advantages and disadvantages of multiple cell membrane coating techniques.

Method	Advantage	Disadvantage	Ref.
Extrusion	Uniformity of dimensions and wide range of applications.	Difficulty in generating large-scale production, possible disruption of membrane structure.	[[204], [205], [206],260]
Sonication	Convenient operation.	Mapping conditions required, possible disruption of membrane structure, particle size inhomogeneity.	[206,207,214,261]
Electroporation	High throughput, high efficiency, maintains membrane integrity and stability, good reproducibility, large-scale production.	High cost, parameters need to be optimized, not suitable for large particles, requires specific equipment.	[211,212]
In situ production	Cell membrane structural integrity, good biocompatibility.	Complex operational processes, inefficient incorporation.	[213]

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Accordingly, there have been notable advancements in the field of cell membrane-encapsulated NPs in recent years. Fig. 6B illustrates the various fusion strategies employed to prepare biomimetic nanocarriers. However, several challenges must be addressed before clinical translation, including intricate preparation procedures, immunogenicity concerns, limited reproducibility, preservation of intact protein structures within the cell membrane, and numerous other unresolved issues.

4.3. CAR-M therapy

Among a wide variety of immunotherapies, adoptive cell therapy (ACT) has gained momentum owing to its capacity for highly targeted and personalized treatment [214]. As a representative ACT, CAR-T cell therapy has considerably advanced individualized cancer treatment [215]. However, despite the strong therapeutic capacity of CAR-T cells for hematologic malignancies, special features such as the lack of tumor-specific antigens, limited adaptability and survival of T cells, and high complexity of the immunosuppressive TME have resulted in low therapeutic success of CAR-T cells in solid tumors [216]. CAR-M cell therapies have emerged to overcome the limitations of CAR-T cells in solid tumors.

Owing to the unique phagocytosis of macrophages and their ability to infiltrate solid tumors, the use of CAR-M to treat solid tumors has been explored [217]. CAR-M therapy involves the delivery of specific CAR genes to macrophages, which recognize the surface of tumor cells through specific antigen identification and the subsequent activation of macrophage activity against cancer cells, resulting in tumor cell death. Although CAR-M and CAR-T share some common limitations, CAR-M therapy has unique advantages in treating solid tumors (Fig. 7): (1) CAR-M does not decay in the TME and has an enhanced antitumor function [218]; (2) CAR-M1 can reverse the M2 phenotype and polarize it toward the M1-type; however, CAR-M2 cannot induce repolarization of the M2-type [219]; (3) CAR-M cells have greater tumor infiltration capacity and provide better resistance to the suppressive TME [220]; (4) In addition to phagocytosis, CAR-M increases T cell cytotoxicity by promoting antigen presentation; (5) The expansion capacity and circulation time of CAR-Ms are limited in vivo, indicating a low possibility of graft-versus-host disease [221]; No adverse side effects were observed, with only a few mild reactions, including fever, weight loss, and other symptoms [222]; (6) Compared with CAR-T cells, CAR-M cells have a wider range of cell sources, decreasing costs and increasing production. Hence, CAR-M cell therapy, as a novel antitumor treatment strategy, offers new possibilities for the treatment of solid tumors.

Various attempts at utilizing CAR-M therapy for cancer immunotherapy have been reported. Klichinsky et al. have demonstrated that CAR-M cells exhibit antigen-specific phagocytosis and tumor clearance in vitro. Furthermore, these cells maintained their pro-inflammatory phenotype and remodeled the TME into a pro-inflammatory state in vivo [223]. The different intracellular signaling structural domains of CAR can affect the antitumor activity of CAR-M itself. Different intracellular signaling domains for CAR were designed to improve the phagocytosis and killing ability of CAR-M cells [224]. Upon comparing the ability of three different intracellular signaling domains (FcRγ, Megf10, and PI3K), CAR-M with the FcRγ structural domain exhibited more powerful phagocytosis and tumor-killing ability [224]. Additionally, CAR-M with FcRγ structural domain showed superior phagocytosis capacity to other CAR-Ms [225]. Furthermore, a new strategy has recently emerged to deliver therapeutic substances (such as antibodies and chemotherapeutic agents) by exploiting the tumor-homing tendency of macrophages. This approach not only enhances the antitumor effects of CAR-M but also reduces the toxic effects associated with systemic administration [226]. For example, macrophages secreting anti-EGFR antibodies could effectively phagocytose EGFR-expressing tumor cells through an antibody-dependent mechanism [227]. In addition, CAR-Ms can be used to release cargo into specific environments. A photoreactive macrophage-controlled CAR-M DDS was constructed to cross the BBB and deliver agents to the central nervous system, inhibiting the polarization of M1-type microglia for sustained anti-inflammatory effects [228].

To date, numerous clinical trials have evaluated the effectiveness of CAR-M cell-based therapeutic strategies in the treatment of solid tumors (Table 6). Based on the promising preclinical results, the FDA has approved CT-0508 for treating HER2+ solid tumors [229]. CAR-Ms carrying scFv targeting HER2 were modified with the chimeric adenoviral vector Ad5f35 to treat 18 patients with relapsed/refractory tumors overexpressing HER2. This is the first clinically available CAR-M therapy for HER2+ solid tumors (NCT04660929) [230]. Another clinical trial evaluating the safety and efficacy of human HER2-modified CAR-M cells in patients with advanced HER2+ gastric and breast cancers has also demonstrated clinical feasibility (NCT05007379).

Table 6.

Clinical trials of the CAR-M-based therapeutic strategies for solid tumors.

Study tittle	Diseases targeted	Drug	NCT identifier	Status
CAR-macrophages for the treatment of HER2 overexpressing solid tumors	HER2-positive recurrent or metastatic solid tumors	CT-0508	NCT04660929	Recruiting
Intraperitoneal MCY-M11 (mesothelin-targeting CAR) for treatment of advanced ovarian cancer and peritoneal mesothelioma	Ovarian cancer, recurrent peritoneal mesothelioma	MCY-M11 and cyclophosphamide	NCT03608618	Terminated (no results posted yet)
Cohort study to determine the antitumor activity of new CAR-macrophages in breast cancer patients' derived organoids	Breast cancer	HER-2 CAR-M	NCT05007379	Not yet recruiting
Human HER2-targeted macrophages therapy for HER2-positive advanced gastric cancer with peritoneal metastases	Advanced peritoneal metastatic gastric cancer	HER-2 CAR-M	NCT06224738	Not yet recruiting
A study of TAK-102 in adult with previously-treated solid tumors	Solid tumors	TAK-102	NCT04405778	Active, not recruiting
A study of TAK-103 in adult with solid tumors	Advanced or metastatic solid tumors	TAK-103	NCT05164666	Active, not recruiting

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CAR-M, as an innovative antitumor strategy, exhibits immense potential as a potent therapeutic intervention against cancer; however, several challenges remain unresolved. First, although CAR-M therapy has achieved notable results in animal models, the human TME is more complex than that in animals. Further research is required to achieve clinical translation. Second, exogenous macrophages are mostly retained in the liver post-injection, which can greatly affect their anticancer therapeutic effect [231]. CAR-M therapy is still in its infancy, with limited clinical experience, and the safety and efficacy of CAR-M remain to be evaluated. Overcoming these shortcomings would advance CAR-M cell therapy as a promising antitumor therapy.

Collectively, the strategies discussed in this section— live macrophages as delivery carriers, macrophage membrane-derived biomimetic NPs, and CAR-M therapy—are based on the inherent tumor-homing properties and phagocytic capabilities of macrophages, with modifications aimed at enhancing therapeutic efficacy. Beyond passive targeting, active targeting is crucial for ensuring that DDSs effectively reach the TME. Basic targeting strategies include modification of targeted peptides. Additionally, designing stimuli-responsive release mechanisms based on low pH, high enzyme activity, and redox state in tumors can further improve tumor specificity. Finally, genetic engineering remains one of the most promising approaches as it enhances the drug delivery efficiency of macrophages through targeted gene modifications [232].

5. Macrophage-derived extracellular vesicles

Recently, EVs derived from immune cells have garnered substantial interest owing to their multifaceted roles in biological processes, functions, and therapeutic potential in various diseases. Compared with other nanocarrier DDS, macrophage-derived extracellular vesicles (M-EVs) possess the following advantages: (1) M-EVs can participate in and influence different biological processes, including cell proliferation, cell migration and cancer development [[233], [234], [235]]; (2) As endogenous nanovesicles, EVs have the advantages of excellent biocompatibility, low immunogenicity, nontoxicity, and high stability [236]; (3) EVs can cross tissue and cellular barriers, including the BBB and endothelial barrier [237,238]; (4) Macrophages have a strong phagocytic ability; therefore, M-EVs have a higher drug-loading efficiency [239]; (5) Unlike artificial NPs, CD47 was highly expressed on the surface of EVs [240]. They release signals by binding to SIRPα to avoid phagocytosis by the mononuclear phagocyte system [241]. Consequently, harnessing M-EVs as novel drug delivery vectors holds considerable promise for cancer treatment, highlighting their unique therapeutic significance.

As macrophages have two polarized states, the function and properties of M-EVs are affected by macrophage polarization and exhibit two phenotypes. M2-derived EVs (M2-EVs) exert a positive effect on repairing damaged cells and tissues. M2-EVs reportedly improve angiogenesis and tissue repair during wound healing by reducing the secretion of pro-inflammatory cytokines such as TNF-α [242]. However, regarding cancer progression, M2-EVs generally facilitate tumor progression by inhibiting apoptosis, increasing drug resistance, stimulating cell proliferation and angiogenesis, promoting immune evasion, and enhancing tumor growth and metastasis [57,243,244]. M2-like TAM-derived exosomes exhibit notable PD-L1 enrichment and interact with CD8⁺ T cells, thereby exerting suppressive effects on antitumor immunity [245]. Conversely, M1-derived EVs (M1-EVs) block immune checkpoints and hinder tumor cell proliferation. For example, M1-exosomes (M1-Exo) loaded with miRNA-16–5p specifically target and downregulate PD-L1 expression in gastric cancer (GC) cells. Blockade of the PD-1/PD-L1 checkpoint can lead to T cell activation and inhibit GC proliferation [246]. Furthermore, M1-EVs can exert an antitumor role in breast cancer by inducing macrophage from the M2 to M1 phenotype via the transport of miR-130 and miR-33 [247,248].

M1-EVs exert their antitumor effects by modulating the TME and serve as natural nanocarriers for drug delivery (Fig. 8). They facilitate drug passage through natural barriers while reducing the intrinsic cytotoxicity of the drug, thereby minimizing the adverse effects of drug therapy. For example, the M1-Exo DDS loaded with the chemotherapeutic agent docetaxel exerted pro-inflammatory and drug carrier properties and substantially inhibited the growth and migration of breast cancer cells [249]. Additionally, it promoted the polarization of naïve macrophages toward the M1 phenotype and induced mitochondrial dysfunction to reduce M2 macrophage polarization [249]. Another M1-Exo DDS was developed to combat chemotherapy-resistant pancreatic cancer by co-loading with gemcitabine and deferasirox. This formulation exhibited higher cytotoxicity and therapeutic efficacy than the free chemotherapeutics [250]. Surface modifications have been explored to further enhance the drug-loading capacity and tumor targeting of EVs. For example, aminoethylanisamide-polyethylene glycol (AA-PEG) was incorporated onto the surface of PTX-containing exosomes (exoPTX) to target sigma receptors overexpressed in lung cancer cells. This novel nanoformulation (AA-PEG-exoPTX) demonstrated high loading capacity, active accumulation at the lung cancer site, and potent antitumor efficacy [251]. These approaches have successfully overcome the drawbacks of inadequate chemotherapy targeting, high side effects, and poor toxicity to cancer cells and represent a novel anticancer strategy that effectively combines chemotherapy and immunotherapy.

Despite the excellent anticancer effects of these methods, EV-liposome-hybridized nanovesicles, called hybrid exosomes, have emerged owing to the limitations of current EV extraction techniques, such as low yield and structural incompleteness. Studies have shown that drug-loaded hybrid exosomes exhibit enhanced toxicity toward cancer cells under acidic conditions, thereby improving the drug delivery efficiency in the acidic TME [252]. Engineered exosome-thermosensitive liposome hybrid NPs (gETL-NPs) have been synthesized and demonstrate efficient infiltration into metastatic peritoneal carcinoma tumors and payload release under hypothermic conditions of hyperthermic intraperitoneal chemotherapy. gETL-NPs designed to co-deliver granulocyte-macrophage colony-stimulating factor and docetaxel effectively enhanced drug penetration efficiency and inhibited cancer progression [253]. Accordingly, M-EVs have considerable potential as natural carriers for targeted drug delivery.

Overall, M-EVs act as a double-edged sword, not only regulating tumor growth, angiogenesis, cell proliferation, and apoptosis but also participating in the immune response and release of inflammatory factors, which play distinct roles in different diseases. Owing to their intrinsic antitumor and pro-inflammatory properties, M1-derived EVs contribute to individualized and effective antitumor therapies. Given the limitations of traditional EV extraction methods, such as low yield and limited functionality, there is an urgent need to develop novel isolation techniques that enable the large-scale production and application of M-EVs. Accordingly, M-EVs have a considerable potential for cancer immunotherapy.

6. Conclusions and future perspectives

Macrophages play a crucial role in both innate and adaptive immunity. They can phagocytose and digest cellular debris and pathogens and function as APCs to activate lymphocytes. Therefore, the use of macrophage-based DDSs is highly promising. Strategies to modulate the immunosuppressive TME with TAM as an immunotherapeutic target and the application of macrophage-based DDS in immunotherapy have been described in detail.

TAMs are abundant in various types of tumors and differentiate in response to tumor-secreting chemokines and growth factors, thereby playing a crucial role in tumorigenesis and progression. The extent of TAM infiltration is closely associated with the prognosis of various cancers and the effectiveness of immunotherapy, making TAMs an ideal target for modulating immunotherapeutic approaches. In this review, we discussed several strategies for targeting TAMs that have been implemented in clinical practice. Blocking phagocytic checkpoints such as CD47/SIRPα to restore macrophage phagocytosis represents a classical therapeutic pathway. Additionally, inhibiting TAM recruitment, directly depleting TAM populations, and reprogramming their functional phenotypes have all demonstrated considerable potential in clinical applications; however, these approaches still face notable challenges. Owing to the heterogeneity and plasticity of mononuclear phagocytes in tumors, the recruitment and polarization of macrophages are influenced by multiple factors, resulting in varying degrees of infiltration across different tissues and organs. Therefore, strategies targeting TAMs alone may be insufficient for manipulating the TME [50]. Moreover, many normal tissue cells express similar targets, hindering drug delivery to TAMs and leading to increased off-target effects and toxicity [254]. Nevertheless, not all the targeting strategies were effective. For example, blocking CSF1R and CSF1 with neutralizing antibodies enhanced spontaneous metastasis. Therefore, drug development must consider the status of focal macrophages and the overall tissue environment. Reportedly, cancer recurrence and exacerbation can also occur after cessation of CCL2 inhibitory therapy [255]. This suggests that the TME is yet to be comprehensively explored. Moreover, potential side effects must be carefully considered, along with the suitability of drugs for patients before administration. Better efficacy can be achieved by combining with other immunotherapeutic tools (e.g., ICB) when necessary.

Macrophage-based DDSs have emerged as promising therapeutic tools, given their ability to penetrate the hypoxic regions of tumors and exert specific tumor-homing effects. The unique potential of live macrophages as delivery carriers stems from their tropism toward inflammatory tissues and their ability to traverse physiological barriers. However, the inherent challenges associated with living cells, such as uncontrollable differentiation, rejection, and unexpected responses, limit their mass production for clinical applications [240]. Difficulties in maintaining cell viability, conducting preliminary in vitro studies, and accurately estimating the required dose further hinder large-scale manufacturing for clinical applications. Cell membrane coating technology has emerged as a candidate for addressing the challenges associated with live-cell applications. Currently, macrophage membrane-mediated biomimetic nano-delivery platforms are considered highly promising for targeted immunotherapy. However, their clinical translation is hampered by hurdles, such as the complexity and difficulty in mass production of preparations, the heterogeneity and poor reproducibility of macrophages, and the challenge of ensuring the structural integrity of membrane proteins [187]. Hence, in terms of preliminary research, it is crucial to enhance macrophage monitoring in the TME to deepen our understanding of their biological functions and involvement in immune responses. Additionally, rational utilization of bioimaging technology should be adopted to track drug transport pathways within macrophage-mediated carriers. Furthermore, combining genetic engineering techniques can facilitate the modification of delivery carriers to render them more suitable for individualized cases. Considering mass production, the focus and challenge reside in developing an easy-to-operate and efficient membrane extraction and coating technique to produce NPs with a high coating rate while ensuring their stability and safety. Therefore, it is necessary to develop easy-to-operate and efficient membrane extraction and coating techniques. The long-term stability and safety of NPs, both in vivo and in vitro, should be systematically evaluated. Furthermore, detailed investigations into immune rejection between donors and recipients of the macrophage membranes and other toxic side effects are essential.

In addition to the aforementioned strategies, there have been advancements in the development of CAR-Ms and macrophage-derived EVs. Future research should primarily focus on precision medicine, encompassing disease monitoring and personalized treatment options. Therefore, universal treatment approaches may be unsuitable for all patients. Therefore, efforts are being directed toward overcoming these barriers and developing targeted drug delivery options tailored to individual needs. Macrophages hold considerable promise as key facilitators of personalized treatment of solid tumors, thus offering a broader perspective on their clinical applications.

Conflicts of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Acknowledgments

This manuscript was partially supported by the Foundation of Jilin Science-Technology Committee [20250206003ZP; 20230402042GH, Z.Y.], National Natural Science of China [21HAA01203, Z.Y.; Grant No 82030107, J.G.], and Graduate Innovation Fund of Jilin University (2024CX203, M.S.; 2025CX129, J.C.). The authors would like to thank Yujin Chen, Hainan Overseas Chinese Middle School, Class 29, for assisting with the drawing of the figures. We further acknowledge the support of BioRender.com, which was used to create all the artwork in this manuscript.

Contributor Information

Jiayi Chen, Email: jychen23@mails.jlu.edu.cn.

Jingkai Gu, Email: gujk@jlu.edu.cn.

Zhaogang Yang, Email: zhaogangyang@jlu.edu.cn.

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PERMALINK

Macrophage-centered therapy strategies: A promising weapon in cancer immunotherapy

Simiao Wang

Jiayi Liu

Yaxin Cui

Man Sun

Wei Wang

Jiayi Chen

Jingkai Gu

Zhaogang Yang

Abstract

Graphical abstract

1. Introduction

Fig. 1.

2. Phenotype of macrophages

2.1. Origin of macrophages

Fig. 2.

Fig. 3.

Table 1.

2.2. Classically activated macrophages

2.3. Alternatively activated macrophages

2.4. Tumor associated macrophages (TAMs)

2.5. Tissue-resident macrophages (TRMs)

3. TAM-targeting strategies in tumor immunotherapy

Fig. 4.

Table 2.

3.1. Regulation of phagocytic checkpoints

3.1.1. CD47/ SIRPα checkpoints

3.1.2. PD-1/PD-L1 checkpoints

3.1.3. MHC-I/LILRB1 checkpoints

3.1.4. CD24/Siglec-10 checkpoints

3.1.5. Other checkpoints

3.2. Inhibition of macrophage recruitment

3.3. Depletion of TAMs

3.4. Reprograming TAMs

4. Engineered macrophages as DDSs

Table 3.

Fig. 5.

Fig. 6.

Fig. 7.

4.1. Live macrophages as a therapeutic strategy

Table 4.

4.2. Macrophage membrane-derived biomimetic nanocarriers

4.2.1. Synthetic NPs derived from macrophages

4.2.2. NPs encapsulated with macrophage membranes

Table 5.

4.3. CAR-M therapy

Table 6.

5. Macrophage-derived extracellular vesicles

Fig. 8.

6. Conclusions and future perspectives

Conflicts of interest

Acknowledgments

Contributor Information

References

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