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[3,4]
cells (non-cellular components of extracellular matrix), and soluble mediators . Interaction of the tumor
with the components of TME may contribute to the expansion of tumorigenesis stages and may lead to the
induction of chemotherapeutic drug resistance [1,5-7] . Due to the crucial role of TME in malignancy,
understanding how TME affects cancer progression may help uncover the underlying mechanisms of tumor
growth and metastasis.

Myeloid cells constitute the predominant cellular population in TME. They are the most abundant
hematopoietic cells in the human body with various functions, comprise a heterogeneous group of immune
cells such as monocytes, macrophages, and dendritic cells (DCs), and have an important role in regulating T
cell responses . Myeloid cells are the predominant population which establishes an immunosuppressive
[8]
milieu and leads to tumor immune evasion . In the presence of activation signals such as granulocyte
[8]
colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), Fms-like
tyrosine kinase 3-ligand (Flt3-L), chemokine (C-C motif) ligand 2 (CCL2), vascular endothelial growth
factor (VEGF), and S100 calcium-binding protein A8/A9 (S100A8/9) proteins , monocytes and granulocyte
[8]
progenitors undergo terminal differentiation to form mature macrophages, DCs, or granulocytes.
Pathological signals or the presence of immunosuppressive cytokines may trigger an alternative activation
and formation of tumor-associated macrophages (TAMs), tumor-associated DCs, myeloid-derived
suppressor cells (MDSCs), and tumor-associated neutrophils (TANs), as shown in Figure 1. Expansion of
[9]
myeloid cells in the tumor is associated with tumor burden according to various patient studies . There is
also substantial evidence to suggest that myeloid cells within TME are responsible for the suboptimal
therapeutic responses in various cancers.

Role of myeloid cells in shaping tumor progression
Immunoediting, also referred to as the 3Es, as proposed by Dunn and Schreiber, refers to the ability of the
immune system to regulate and shape cancer progression [9,10] . It is a dynamic process involving both
[8]
immune cells and cancer cells . Recognition and elimination of tumor cells by various cells of the innate
and adaptive immune system is the main function of immunoediting. This is carried out in three phases:
elimination, equilibrium, and escape [11,12] . The elimination phase, as the name suggests, denotes the
elimination of tumor cells. The key players in this phase are natural killer cells (NK) and T cells, which
through interferon-γ (IFN-γ) and interleukin-12 (IL-12) production, eliminate the tumor cells. The next and
the longest phase is known as the equilibrium phase, where the immune selection of tumor variants occurs.
Tumors, in turn, continue to incorporate multiple mutations to survive this selection. The last phase, the
escape phase, follows when the tumor variants start to overwhelm the immune response and expand in an
uncontrolled manner, which eventually leads to malignancy. The role of myeloid cells is primarily
important in equilibrium and escape phases. Particularly, TAMs serve as modulators against tumor
immunogenicity; they can be activated by NK cells or T cells . The activity of tumor-infiltrating myeloid
[8]
cells (TIMs) is also enhanced by inhibition of the glycolysis pathway in TAN, TAM, and mature DCs [8,13,14] .

The persistence of cancer along with the immune cells (that have pro- or antitumor properties) in the
escape phase leads to inflammation. The escape phase is the third and final stage, where the tumor becomes
clinically apparent and establishes an immunosuppressive TME . This persistence is supported and further
[15]
sustained by TAMs, TANs, and MDSCs, which are recruited through factors secreted by the tumors (these
[8]
factors and their functions are listed in Table 1) . These three subsets are the key myeloid populations that
are well established in cancers. TAMs and MDSCs are known to exert immunosuppressive functions and
thereby suppress T cell-mediated tumor killing; suppression occurs through a variety of processes, as
detailed in Figure 2B. They recruit Tregs through CCL22 secretion, which also supports the suppression of
immune functions . TANs, on the other hand, do not exhibit suppressive activities, but it has been
[16]
[17]
demonstrated that the elimination of TANs leads to the increased cytotoxic activity of T cells . Conditions