Targeting tumor-associated macrophages to reverse antitumor drug resistance

Therapeutic potential of targeting TAMs

Through investigating the mechanism of TAM reprogramming and resistance induced by TAMs, researchers have produced many new drugs targeting TAMs for tumor treatment. These drugs regulate the immune function of TAMs and induce their transformation in an anti-tumor direction. They are currently primarily applied in combination with chemotherapy, immunotherapy, vascular targeted therapy, and other conventional treatment methods to overcome the resistance of conventional treatment methods and have an adjuvant therapeutic effect. According to the various mechanisms and targets, macrophages can be classified into reducing or depleting TAMs, repolarizing TAMs towards M1-like macrophages, enhancing the immune function of T cells, and other potential therapeutic targets (Figure 1). Additionally, the application of nanotechnology and other biomaterials can help achieve the delivery of drugs targeting TAMs to the tumor site and monitor the immune function of TAMs, which is another important strategy to enhance anti-tumor therapy development.

Figure 1. The therapeutic strategies targeting macrophages have been noticeable in recent years. Single application and combined application with traditional drug therapy have great potential. According to their mechanisms, they are mainly divided into the following categories. Reducing the recruitment of TAMs includes the use of αCSF-1, αCSF-1R, TD-92 (CSF-1R inhibitor), carlumab (αCCR2), maraviroc (CCR5 inhibitor), OLA-PEG (CXCL12 inhibitor), and AMD3100 (CXCR4 inhibitor). Reprogramming TAMs to the M2-like phenotype includes the use of TG100-115 (PI3Kγ inhibitor), poly (I:C) (TLR3 agonist), resiquimod (TLR7/8 agonist), R848 (TLR7/8 agonist), αCD40, and simvastation. TAMs inhibit the T-cell-induced immune response through PD-1/PD-L1, PGE2, IL-10, and TGF-β. The use of αPD-1, αPD-L1, and macrophage targeted therapy may activate T-cell-induced immune response. Blocking the “don’t eat me” signal includes the use of αCD24, magrolimab (αCD47), Rx-001 (both SIRP-α and CD47 inhibitor), and siRNAs against JMJD1A.

Reducing the recruitment of TAMs

The primary approach to reduce the number of TAM infiltrates is to inhibit the recruitment of monocytes. Several preclinical studies demonstrated that chemokine inhibitors reduce TAM infiltration and effectively inhibit tumor progression [41, 115, 116]. The combination of TAM chemokine inhibitors with chemotherapy or immunotherapy has significant potential in tumor treatment. CSF-1, also known as M-CSF, is a key proliferation and differentiation factor for monocyte–macrophage lineages [117, 118] that recruits macrophages to the tumor site and promotes TAM polarization. Therefore, CSF-1/CSF-1R represents a target for the direct or indirect medical intervention of TAMs [78]. A recent preclinical study of CSF-1 inhibition combined with immunotherapy in non-small-cell lung cancer reported that TD-92 (a novel erlotinib derivative) enhanced the antitumor effect of PD-1 blocker by downregulating CSF-1R and depleting TAMs in the TME [119]. Other animal experiments demonstrated that the introduction of CSF-1R inhibitors after anti-VEGF drug resistance reduced the tumor size to little or no measurable degree in high-grade serous ovarian cancer [120]. To simulate clinically adaptive conditions, mice were treated with bevacizumab and paclitaxel until the emergence of resistance, then CSF-1R inhibitors markedly attenuated the function of macrophages and restored the response to anti-angiogenesis treatment, thus causing robust anti-tumor effects [120]. In addition to CSF-1, both CCL2 and CCL5, as two important chemokine ligands, have an important role in TAM recruitment. Many scholars have investigated them as targets to inhibit TAMs, but most of their impacts were negative [121–123]. Additionally, blocking the chemokine-receptor axis CXCR4/CXCL12 inhibited the recruitment of TAMs. For example, introducing an SDF-1α (CXCL-12) inhibitor to anti-VEGF antibodies significantly reduced the level of TAMs and prolonged the survival time of glioblastoma-bearing rodents compared with the VEGF blockade alone [116]. Inhibiting CXCR4-dependent immunosuppressive monocytes similarly enhanced anti-angiogenic therapy in colorectal cancer by regulating the recruitment of these myeloid cells [124].

Reprogramming TAMs to M1-like phenotype

Chemokines can activate phosphoinositol 3-kinase γ subtype (PI3Kγ) in myeloid cells within the TME, thus promoting the recruitment of monocytes to tumor sites, and are closely related to the M2-type polarization of TAMs [125]. In the past few years, the inhibition of PI3Kγ to assist other drugs in tumor treatment has gained widespread attention. An animal experiment has proven that the combination of PI3Kγ inhibitor and temozolomide in the treatment of glioblastoma overcame the resistance of temozolomide and enhanced the anti-tumor effect [126]. Poly (l-glutamic acid)-combretastatin A4 conjugate (PLG-CA4), as a novel class of vascular disrupting agents (VDAs), can induce the polarization of TAMs towards the M2-like phenotype in breast cancer. Compared to the monotherapy of PLG-CA4, the combination of PLG-CA4 and PI3Kγ inhibitor potentially enhances the impact of cytotoxic T lymphocytes and significantly extends the mean survival time through decreasing the number of M2-like TAMs [127]. TLRs are important pathogen recognition receptors expressed by immune system cells. The stimulations to TLR3, TLR4, TLR7/8, and TLR9 lead to the rapid activation of innate and adaptive immunity. A recent study observed that some M1-type markers (CD86, CD80, and CD40) were upregulated in macrophages in response to TLR3 stimulation both in vivo and in vitro, while M2-type specific indicators such as CD206 decreased [128]. Fibrosarcoma mice treated with a combination of TLR3 agonist poly (I:C) and TLR7/8 agonist resiquimod demonstrated increased M1 macrophages, decreased M2 macrophages, and increased infiltration of CD8+T cells and CD4+T cells. Compared with single TLR agonist treatment, the impact of the above combined treatment was more significant, and the anti-tumor effect was significantly better [129]. Several studies have demonstrated that oxaliplatin resistance is primarily related to the reduction in myeloid derived suppressor cells (MDSCs) and their differentiation into M1-type macrophages. Treatment with TLR7/8 agonist combined with oxaliplatin can significantly promote the differentiation of MDSCs into M1-type macrophages, thus overcoming drug resistance [130]. Additionally, researchers have used nanoscale metal–organic frameworks (nMOFs) to co-deliver TLR7 and CD47 antibodies to the tumor site and cooperated with PD-L1 immune checkpoint inhibitors to treat colorectal cancer. This repolarized M2-like macrophages into the M1 type, achieving excellent anti-tumor efficacy [131]. The cell surface molecule CD40 is a highly conserved costimulatory protein on antigen presenting cells. Recent studies have reported that agonistic CD40 antibodies can activate macrophages and promote the repolarization of TAMs to M1 type, thus enhancing anti-tumor immune responses [132–134]. In preclinical studies, the combination of CD40 agonist antibodies and imatinib in gastrointestinal stromal tumor treatment promoted TAMs towards the M1 type, significantly overcoming resistance to tyrosine kinase inhibitors individually [135]. Poly (ADP-ribose) polymerase inhibitor (PARPi) is approved for the treatment of ovarian or breast cancers with BRCA1/2 mutations (BRCAmut), many studies have demonstrated that PARPi olaparib could cause reprogramming of TAMs to higher cytotoxicity and phagocytosis with anti-tumor efficacy [136]. Researchers have found olaparib induce increased glycolysis and oxidative phosphorylation, leading to more reactive oxygen species (ROS) and TAMs transcriptional reprogramming. Further analysis has revealed that administration of CD47 antibodies combined with olaparib may improve tumor control [137]. In addition to the typical targets above, one preclinical study suggested the application of the cholesterol-lowering drug simvastatin to reduce cholesterol synthesis [138]. On the one hand, it inhibits the lipid raft/integrin/FAK pathway; on the other hand, it inhibits the cholesterol-dependent LXR/ABCA1 mechanism (hepatic X receptor/ATP-binding cassette transporter A1), repolarizing TAMs, thus reducing the generation of TGFβ. The two mechanisms jointly overcome the paclitaxel resistance induced by epithelial–mesenchymal transition (EMT). Paclitaxel combined with simvastatin in non-small-cell lung cancer treatment achieved good efficacy.

Targets of activating T-cell-induced immune response

Macrophages, as innate immune cells, present antigens to stimulate the activation signal of T cells and are potent effector cells that activate adaptive immune responses [139–141]. However, the infiltration of M2-like TAMs results in an immunosuppressive TME that inhibits the activation of cytotoxic T lymphocytes during tumor treatment [142–144]. This can be achieved through expression of inhibitory immune checkpoint molecules, including PD-L1 [145] and secretion of immunosuppressive cytokines (including IL-10, TGF-β, prostaglandin E2) [146]. Through the therapeutic targeting of anti-inflammatory TAMs, the disinhibition of CD8+ T-cell-dependent immune responses may enhance the therapeutic efficacy of vascular-targeted therapies. The CCL2/CCR2 axis mediates TAM infiltration, while the application of a natural CCR2 antagonist decreased the number of TAMs in the tumor stroma and shifted them towards the M1-like phenotype, further elevating the number of CD8+ T cells [147]. The CCR2 antagonist, combined with low-dose sorafenib, potentiated anti-liver tumor effects via upregulating intratumoral CD8+ T cells and enhanced the distribution of CD8+ T cells in the tumor milieu, without obvious toxicity [147]. C-C motif chemokine receptor-like 2 (CCRL2) is a nonsignaling atypical receptor cloned from LPS-activated macrophages. Clinical data indicate that melanoma patients with high CCRL2 expression exhibit increased infiltration of CD8+T cells with stronger antitumor activity. Researchers have proven that CCRL2 retains TLR4 on the surface of the macrophage membrane via animal experiments and then activates macrophages to the M1 phenotype via the Myd88-NFκB signaling pathways. It amplifies the antitumor response of CD8 + T cells, and CCRL2 may thus be a potential target for cancer immunotherapy [148]. A recent preclinical study on the CSF-1/CSF-1R inhibitor pexidartinib in the treatment of sarcoma demonstrated that, in addition to decreasing TAM infiltration and phenotypic changes from M2 to M1, increased CD8+T cell infiltration and decreased Treg cell infiltration were observed in the TME post-treatment. These results may offer a reference for antitumor therapy targeting macrophages to enhance CD8+T cell activity [149]. CXCL12/CXCR4 is a key signaling pathway that recruits TAMs, and the blockade of the CXCL12/CXCR4 possesses great potential for cancer treatment [150]. A recent preclinical study on hepatocellular carcinoma demonstrated that a novel CXCR4 antagonist combined with sorafenib increased cytotoxic CD8+ T cell infiltration more significantly, and the overall survival was more remarkably extended than using sorafenib alone [150]. Such a combination based on the relief of TAM-mediated immunosuppression enhanced the anti-tumor function of vascular-targeted therapy. Currently, the blockade of immune checkpoint signals has demonstrated durable therapeutic responses in clinics [151]. Although these immunotherapies have demonstrated great potential to treat tumors, immune checkpoint inhibitors only function when CD8+ T cell are infiltrated within the TME [152]. Numerous studies have shown that the repolarization of macrophages to the M1 phenotype restores the infiltration and cytotoxicity of CD8+ T cells, thus limiting tumor progression and metastasis [151–153]. Adding checkpoint inhibitors to the combination between vascular-targeted agents and vascular-targeted therapy may yield improved clinical benefits. A preclinical study investigated the application of CSF-1R inhibitors PLX3397 (pexidartinib) and PLX5622 in combination with anti-PD-1 immunotherapy in lung squamous cell carcinoma. The inhibition of CSF-1R reduced the infiltration of macrophages at the tumor site, inhibited the activity of CD8+T cells by M2 macrophages, and enhanced the migration and infiltration of CD8+T cells into tumor islets. Its combination with anti-PD-1 therapies further increased the close contact between CD8+T and tumor cells, eventually delaying tumor progression [154].

Other potential molecular targets

CD24 and CD47 are two types of membrane proteins broadly expressed by tumor cells, which can bind to signal proteins on the surface of macrophages, trigger the “don’t eat me” signal, and inhibit macrophage phagocytosis, thus escaping anti-tumor immunity. Therefore, the inhibition of CD24 and CD47 has become a new strategy of anti-tumor immunotherapies and has prompted great research potential in recent years. Preclinical studies have demonstrated that CD24 promotes immune evasion in ovarian cancer and triple-negative breast cancer by interacting with the inhibitory receptor sialic acid binding ig-like lectin 10 (Siglec-10) expressed by tumor-associated macrophages (TAMs). Both genetic ablation of CD24 or Siglec-10 and the monoclonal antibody blockade of the CD24–Siglec-10 interaction enhance the phagocytosis of macrophages to tumor cells, inhibit tumor growth, and prolong overall survival time [155]. A research team developed a CD47 mAb using hybridoma technology and tested it in preclinical studies. It was combined with a standard chemotherapy regimen to treat mice with triple-negative breast cancer and significantly inhibited tumor growth [156]. Another preclinical study demonstrated that the combination of CD47 mAb Hu5F9-G4 and trastuzumab in the treatment of Her2+ breast cancer cells significantly overcame the resistance to trastuzumab monotherapy and effectively inhibited tumor growth [157]. CD24 inhibits the antitumor effect of macrophages by binding to signal-regulatory protein alpha (SIRPα) on the surface of macrophages. Transcription factor ZBTB28 is a tumor suppressor with extensive expression in normal tissue. A series of preclinical studies have demonstrated that the gene expression of CD24 and CD47 is beneficial to increase the anti-tumor phagocytosis of macrophages. However, the gene is always silent in breast cancer, so activating this gene can have a significant anti-tumor effect. This study provides novel ideas and research directions for the immunotherapy of breast cancer [158]. In addition to the two targets above, researchers have reported several unique targets for macrophage therapy in the field of vascular targeted therapy, which are mechanistically suitable for the combined application with vascular targeted therapy. Following the management of vascular-targeted therapies, hypoxia and nutrient starvation collaborate to prompt aggressive properties that resist anti-angiogenic attacks [159, 160]. Recent research has thus focused on alleviating hypoxia outcomes or even normalizing the tumor vasculature to improve anti-angiogenic therapy. Microarray analysis identified in vitro upregulation of the functional driver JMJD1A, a histone demethylase, under long-term hypoxic conditions and in vivo prior to the activation of angiogenesis or the refractory phase of anti-angiogenic drugs [161]. JMJD1A inhibition explicitly suppressed tumor progression by decreasing macrophage infiltration and the angiogenic switch, thus enhancing the anti-tumor effects of anti-VEGF agents [161]. The medical inhibition of the VEGF/VEGFR pathway failed to prolong overall survival in patients with glioblastoma [162, 163], and studies demonstrated that circulating Ang-2 levels rebounded after the administration of the pan-VEGFR inhibitor cediranib [164]. Moreover, combination therapy using cediranib and an anti-Ang-2 neutralizing antibody morphologically and structurally transformed and normalized the highly aberrant and dysfunctional tumor vessel network [165]. Dual targeting of Ang-2 and the VEGF pathway reshaped the pro-tumor M2 subtype towards anti-tumor M1 macrophages, thus reducing the tumor burden and mediating survival benefits in glioblastoma [165, 166].

The clinical trials of TAM-targeting therapy

Clinical trials have recently been completed for a variety of drugs targeting TAMs (Table 3). The targets of TAMs mainly include CSF-1R, CCL, CD40, TLR, PI3Kγ, and CD47, most of them are in phase I clinical trials with good therapeutic efficacy. Among the drugs that inhibit the recruitment of TAMs, the CSF-1R inhibitor pexidartinib in clinical trials has excellent clinical benefits in solid tumors such as in tenosynovial giant-cell tumors (TGCT), unresectable sarcoma, and malignant peripheral nerve sheath tumors. The current study has found that pexidartinib combined with paclitaxel result in a completed remission (CR) rate of 3% and a partial remission (PR) of 13%. Especially, the most promising signal of clinical activity has been noted in patients with platinum-resistant or -refractory epithelial gynecologic malignancies, which patients have experienced a CR. Moreover, the phase III trial of pexidartinib for the treatment of TGCT has been completed [167–169]. The clinical trial has shown that Pexidartinib is shown a robust tumour response in TGCT with improved patient symptoms and functional outcomes and could be considered as a potential treatment. Emactuzumab (CSF-1R inhibitor) has also shown excellent efficacy against TGCT [170] but has shown poor efficacy against other solid tumors [171–173]. In addition, surufatinib, which targets CSF-1R, has shown encouraging antitumor activity in the treatment of well-differentiated neuroendocrine tumors. Currently, the phase II trial of surufatinib has been completed, and other two phase III trials are ongoing [174]. The trial of ARRY-382 (CSF-1R inhibitor) combined with pembrolizumab (PD-1 monoclonal antibody) for solid tumors has not demonstrated positive efficacy [175]. In addition, other targets that inhibit recruitment CCL2 and CCL5 have good tolerance but poor anti-tumor activity in clinical trials [121–123, 176].

Table 3. Clinical trials of TAMs targeted therapies.

Targets	Drugs	Phase	Tumor	Status	Time	NCT
CSF-1	PD-0360324	Ib/II	Advanced Cancer	Active	2015.11.9-present	NCT02554812
CSF-1R	JNJ-40346527	I	Relapsed or Refractory Hodgkin Lymphoma	Completed	2012.7.17-2013.8.13	NCT01572519
		I	Prostate Adenocarcinoma	Active	2017.6.7-present	NCT03177460
		II	Acute Myeloid Leukemia	Terminated	2018.10.5-2020.9.28	NCT03557970
	TPX-0022	I/II	Solid Tumor	Recruiting	2019.9.21-present	NCT03993873
	Cabiralizumab	I	Advanced Solid Tumor	Completed	2015.9.8-2019.11.18	NCT02526017
		II	Advanced Pancreatic Cancer	Active	2017.12.19-present	NCT03336216
		I	Advanced Malignancies	Completed	2017.5.25-2019.10.23	NCT03158272
		I	Cancer	Active	2018.3.15-present	NCT03431948
		I	Advanced Cancer	Completed	2018.5.7-2021.3.31	NCT03335540
		I	Advanced Melanoma and non-small Cell Lung Cancer, renal Cell Carcinoma	Active	2018.6.9-present	NCT03502330
		II	Pancreatic Cancer	Terminated	2018.7.31-2020.6.15	NCT03599362
		II	Pancreatic Cancer	Suspended	2019.10.31-present	NCT03697564
		II	Peripheral T Cell Lymphoma	Active	2019.4.25-present	NCT03927105
		II	Hepatocellular Carcinoma	Active	2019.9.12-present	NCT04050462
		I/II	Triple Negative Breast Cancer	Recruiting	2020.11.19-present	NCT04331067
		II	Head and Neck Squamous Cell Carcinoma	Recruiting	2021.4.24-present	NCT04848116
	IMC-CS4	I	Advanced Solid Tumor	Completed	2011.6.1-2018.5.31	NCT01346358
		I	Pancreatic Cancer	Active	2018.9.27-present	NCT03153410
	SNDX-6352	I	Solid Tumor	Completed	2017.9.1-2020.11.20	NCT03238027
		II	Unresectable Intrahepatic Cholangiocarcinoma	Active	2021.8.24-present	NCT04301778
	BLZ945	I/II	Advanced Solid Tumor	Terminated	2016.10.21-2022.12.1	NCT02829723
	DCC-3014	I/II	Advanced Malignant Neoplasm Pigmented Villonodular Synovitis Giant Cell Tumor of Tendon Sheath	Recruiting	2017.2.16-present	NCT03069469
		III	Tenosynovial Giant Cell Tumor	Recruiting	2021.10.14-present	NCT05059262
	ARRY-382	Ib/II	Solid Tumor	Completed	2016.9-2019.10	NCT02880371
	PLX73086	I	Solid Tumor	Terminated	2016.2.1-2018.1	NCT02673736
	Emactuzumab	Ib	Combine with Atezolizumab in Advanced Solid Tumor	Completed	2015.1.19-2020.8.21	NCT02323191
		Ib	Combine with Selicrelumab in Solid Tumor	Completed	2016.5.9-2018.4.6	NCT02760797
		I	Combine with Paclitaxel in Solid Tumor	Completed	2011.12.20-2018.2.7	NCT01494688
		III	Tenosynovial Giant Cell Tumor	Active	2022.7.18-present	NCT05417789
	PLX3397	III	Tenosynovial Giant Cell Tumor	Completed	2015.5-2016.9	NCT02371369
		II	Recurrent Glioblastoma	Completed	2011.12.3-2013.11.5	NCT01349036
		I/II	Tenosynovial Giant Cell Tumor	Completed	2012.9-2014.4	NCT01004861
		I	Combine with Sirolimus in Unresectable Sarcoma and Malignant Peripheral Nerve Sheath Tumor	Completed	2015.4-2018.9	NCT02584647
		I	Combine with MEK162 in Gastrointestinal Stromal Tumor	Completed	2017.4.15-2021.4.28	NCT03158103
CCR2	MLN1202	II	Metastatic Cancer	Completed	2010.3.1-2012.12	NCT01015560
		I	Melanoma	Terminated	2016.6.22-2018.5.11	NCT02723006
	PF-04136309	II	Metastatic Pancreatic Ductal Adenocarcinoma	Terminated	2016.5.4-2017.9.15	NCT02732938
		I	Pancreatic Neoplasms	Completed	2012.4-2013.10	NCT01413022
	CCX872-B	I	Pancreas Cancer	Completed	2015.2.1-2020.5.6	NCT02345408
CCL2	Carlumab	Ib	Solid Tumor	Completed	2010.5-2010.11	NCT01204996
		II	Metastatic Castration-Resistant Prostate Cancer	Completed	2009.9-2011.11	NCT00992186
CCL5	Maraviroc	I	Colorectal cancer	Completed	2018.5-2018.11	NCT03274804
CXCR4	AMD3100	I	Pediatric Acute Myeloblastic Leukemia and Lymphoblastic Leukemia	Terminated	2012.6-2014.4	NCT01655875
		I/II	Acute Myeloid Leukemia	Completed	2007.7.1-2010.6	NCT00512252
PI3Kγ	BYL719	III	Advanced HER2+ Breast Cancer	Active	2020.7.16-present	NCT04208178
		I	Ovarian Cancer, Breast Cancer	Completed	2012.9.1-2019.5	NCT01623349
	BKM120	I	Carcinoma, Non-Small-Cell Lung	Completed	2013.4.1-2017.10.17	NCT02128724
		II	High Risk Prostate Cancer	Terminated	2013.4.23-2015.2.5	NCT01695473
		I	Breast Cancer	Completed	2012.10.1-2014.2	NCT01513356
TLR-8	Motolimod	Ib	Combine with Cetuximab in Head and Neck Squamous Cell Carcinoma	Completed	2014.10.28-2016.8.11	NCT02124850
TLR-7/8	R848	I	Melanoma (Skin)	Completed	2006.4.1-2011.10	NCT00470379
		I/II	Nodular Basal Cell Carcinoma	Terminated	2013.2.1-2013.8	NCT01808950
CD40	ABBV-428	I	Solid Tumor	Completed	2016.11-2018.6	NCT02955251
	Selicrelumab	I	Resectable Pancreatic Cancer	Completed	2015.10-2018.11	NCT02588443
	Sotigalimab	II	Combine with Nivolumab in Metastatic Pancreatic Cancer	Completed	2018.8-2019.6	NCT03214250
	APX005M	I	Combine with Cabiralizumab with or without Nivolumab in Melanoma, Kidney Cancer, or Non–Small Cell Lung Cancer	Completed	2018.6-2019.4	NCT03502330
	ADC-1013	I/II	Metastatic Pancreatic Ductal Adenocarcinoma	Recruiting	2021.9.17-present	NCT04888312
		I	Solid Tumor	Completed	2015.4.1-2017.3.8	NCT02379741
		I	Solid Tumor	Completed	2015.4-2016.12	NCT02379741
	Chi Lob 7/4	I	Non-Hodgkin Lymphoma	Completed	2007.7.1-2014.10	NCT01561911
CD47	Hu5F9-G4	Ib	Relapsed or Refractory non-Hodgkin’s Lymphoma	Completed	2016.10-2017.11	NCT02953509
	CC-90002	I	Relapsed/Refractory Acute Myeloid Leukemia or High-risk Myelodysplastic Syndromes.	Completed	2016.3-2018.7	NCT02641002
SIRP-α	TTI-621	I	Relapsed or Refractory Hematologic Malignancies	Completed	2016.1.31-2022.12.31	NCT02663518
CD47 and SIRP-α	RRx-001	I	Advanced, Malignant, Incurable Solid Tumor	Completed	2011.10-2013.3	NCT01359982
		I/II	Brain Metastases	Completed	2015.2.6-2016.11.28	NCT02215512
		II	Colorectal Cancer	Completed	2014.5-2018.4.13	NCT02096354

Besides inhibiting the recruitment of TAMs, regulating the repolarization of M2-type TAMs and targeting CD40 have also been tested in clinical trials [177–179]. Duvelisib, a PI3Kγ inhibitor, has shown promising clinical benefits in phase I trials, and the phase II and III trials are being further studied [180, 181]. Clinical responses have been seen across a range of doses and disease subtypes: iNHL overall response rate 58%; relapsed/refractory CLL 56%; peripheral TCL 50%; and cutaneous TCL 32%. In addition, as a dual inhibitor of SIRP-α and CD47, RRx-001 has shown excellent efficacy in the studies of solid tumors such as brain metastases, small cell carcinoma, and colorectal cancer. At present, some phase II trials of RRx-001 have been completed with promising efficacy [182–184]. Hu5F9-G4, TTI-621, and other drugs targeting CD47 have also shown good clinical activity in phase I trials [185–187]. In terms of safety, most of drugs have shown tolerable adverse side effects, with only fatigue, pruritus, headache, nausea, vomiting, edema, and other common adverse reactions reported. In some drug trials targeting CSF-1R, patients showed elevated liver enzymes, which may be related to the destruction of Kupffer cells in the liver [167, 173, 174]. Meanwhile, some clinical trials of hematological tumors and highly malignant endocrine tumors have shown changes in the blood system such as neutropenia and lymphopenia [168, 174, 180]. In addition, the results of phase III clinical trials of PLX3397 have shown obvious hepatotoxicity, which may be related to the expression of CSF-1R in Kupffer cells in the liver [167].

Clinical trials targeting TAMs with positive clinical efficacy have not been observed, and we summarize the reasons as follows. Firstly, the main purpose of phase I trials is to test the safety of drugs, so the groups are often divided by dose escalation, which leads to a small number of cases in the high-dose group to achieve therapeutic effect. Therefore, researchers suggest to increase the dosage of the drugs if patients in clinical trials can tolerate the side effects [173, 175, 188]. Secondly, some patients stopped the trial because of obvious adverse reactions in phase I trials, leading to only a small sample size and no meaningful efficacy evaluation [189]. Therefore, it may be necessary to further increase the sample size or seek means to reduce drug toxicity. Thirdly, some drugs are off-target, so they cannot effectively target TAMs [121–123, 172, 176]. The off-target effect also has an impact on normal immune response, such as infections, autoimmunity, and cancer. Some studies have analyzed that the drug concentration in peripheral blood may be low due to the M2-type TAMs in the skin [172]. Thus, it is necessary to further analyze its pharmacokinetics and pharmacodynamics in order to improve drug development.

Author Contributions

Hanjiao Qin and Dan Zhang performed literature search. Sheng Li and Jiyao Sheng wrote the manuscript. Hanjiao Qin drafted the figures. All authors read and approved the final manuscript.

Conflicts of Interest

The authors declare no conflicts of interest related to this study.

Funding

This work was supported by grants from Natural Science Foundation of China (82002809), and Medical and Health Talents Project of Jilin Province (2020SCZT097).

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