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Balakrishnan et al. J Cancer Metastasis Treat 2022;8:27 https://dx.doi.org/10.20517/2394-4722.2022.33 Page 7 of 17

[23]
macrophages and cancer cells can also promote tumor survival .

Experiments have shed light on therapies directed toward TAMs. For example, RT has been shown to
[64]
influence the M1 phenotype in TAMs . Conversely, chemotherapies are hindered by TAMs; for example,
in the case of treatment with paclitaxel, an accumulation of TAMs was observed, which led to the failure of
the therapy due to acquired resistance .
[65]
Treatment strategies usually focus on CCL2 and CSF-1 as they are the key players in TAM recruitment;
inhibition of CSF-1R impacts the level of TAMs in tumors and reduces their immunosuppressive functions.
Humanized CSF-1R antibody emactuzumab has shown positive results [66,67] . CCL2 blockade combination
trials are underway as well . Furthermore, program death ligand-1 (PD-L1) expression on TAMs
[67]
promoted tumor growth, and TAM-specific PD-L1 inhibition has been demonstrated to induce a reduction
[68]
in tumor growth .
New therapeutics using the RNAi (RNA interference) delivery system have been shown to be quite
beneficial. The systems for targeting TAMs are grouped into liposomes, polymers, and inorganic
nanoparticles in Table 3.

Myeloid-derived suppressor cells
MDSCs are heterogeneous cells of myeloid lineage which exhibit immunosuppressive activity. These cells
[26]
have been shown to play a pathological role in cancers and other infectious diseases . An important role
for MDSCs has also been shown in conditions such as aging, pregnancy, and neonates . Overall, MDSCs
[69]
[70]
have been shown to induce immunosuppression in diverse inflammatory conditions . The characteristic
role in disease pathology orchestrated by MDSCs is incompletely understood. In a tumor setting,
myeloblasts receive instructions from tumors to form MDSCs, as shown in Figure 1.

MDSCs have been broadly divided into two major subsets based on cellular, molecular, biochemical, and
functional characteristics. The monocytic MDSC (M-MDSC) is morphologically similar to monocytes,
while the polymorphonuclear MDSC (PMN-MDSC) is morphologically similar to neutrophils [68,71] .
Recruitment of MDSCs to tumor site occurs via G-CSF, GM-CSF, or hypoxia. MDSCs induce
immunosuppressive effects via IL-6, TNF-α, and PGE2 . PMN-MDSCs produce reactive oxygen species
[26]
(ROS), nitric oxide synthase (NOS), and peroxynitrite , which inhibit the T cell functions by inducing
[72]
T cell apoptosis and anergy. PMN-MDSCs inhibit T cell function in an antigen-specific manner. M-MDSCs
inhibit in both antigen-specific and non-specific manners, via production of arginase enzyme, interleukin-
10 (IL-10), cyclooxygenase 2 (COX2), and transforming growth factor beta (TGFβ) [21,72-74] . It has been shown
that tumor progression is also promoted by MDSCs through enhanced production of vascular endothelial
growth factor (VEGF), basic fibroblast growth factor (bFGF), and matrix metallopeptidase 9 (MMP9) .
[75]

The presence of circulating MDSCs has a negative influence on patient outcomes and hampers
immunotherapy, as seen in lung, breast, and colorectal cancer [76-78] . All-trans retinoic acid (ATRA) has been
shown to decrease the number of circulating MDSCs and reduce ROS production [43,44] . Notch signaling
exhibits a controversial role in MDSC biology. In some studies, the accumulation of MDSCs is correlated to
notch signaling [41,42,47] , while others show that inhibition of notch signaling leads to abnormal differentiation
of myeloid cells . PMN-MDSCs show less immunosuppressive effects when notch signaling is blocked .
[42]
[48]
It has also been proposed that notch signaling induces metastasis of cancer by inducing the migration of
MDSCs . Notch receptors function by binding to Jagged or DLL membrane ligands and trigger canonical
[23]
or non-canonical notch signaling pathways . Inhibition of the notch pathway by anti-Jagged antibodies
[79]