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survival (HR = 1.70, 95% CI = 1.39-2.09; P < 0.001). A similar result was demonstrated for M2 macrophage
infiltration (HR = 1.71, 95% CI = 1.19-2.45; P = 0.004). In contrast, elevated M1 macrophage density in GC
patients is associated with better overall survival (HR = 0.46, 95% CI = 0.33-0.65; P < 0.001). This meta-
analysis demonstrated that the numbers of infiltrating M2 macrophages and total TAMs may be negative
prognostic factors for GC patients, while infiltrating M1 macrophages may be associated with a favorable
[41]
survival rate .
The mechanisms of GC progression affected by TAMs have been investigated. Macrophages induce the
capillary formation of lymphatic endothelial cells. Co-culture with GC pretreated macrophages upregulate
lymphangiogenic factors, including inflammatory cytokines, MMPs, adhesion molecules and vascular
endothelial growth factor-C. Interaction between lymphatic endothelial cells and macrophages may be an
[42]
important initial step in tumor lymphangiogenesis developing lymph node metastasis . The high density
of CD163+ TAMs (M2 macrophage) is an independent prognostic marker heralding prolonged disease-free
survival. The prognostic implication of CD163+ TAMs might be determined by the proportional balance of
[43]
TAMs and TILs in MSI-H GCs .

Redox adaptation enables cancer cells to survive under increased oxygen species (ROS) stress. ROS
[44]
produced by TAMs triggers CD44 expression through the suppression of miR-328 in GC cells . Cluster
of differentiation 44 (CD44) is a major adhesion molecule and a broadly distributed cell surface receptor
[45]
for hyaluronic acid . The CD44 gene is located on chromosome 11p13 and contains 20 exons, 10 of which
[46]
are expressed in the standard form (CD44s) . CD44 isoforms, containing variant exon 6 (CD44v6), are
[47]
identified by alternative splicing of at least 12 exons . CD44 variant isoform (CD44v) is one of the cell
[48]
surface markers of GC stem cells . Furthermore, CD44v contributes to defense against reactive ROS by
stabilizing the glutamate-cystine transporter subunit xCT, and promoting the synthesis of the primary
[49]
intracellular antioxidant glutathione .
Epithelial-mesenchymal transition (EMT), which is induced by TAMs, may play a key role in cancer
metastasis. M2 macrophages secrete epidermal growth factor or TGFB, which stimulates EMT [50,51] .
Epidermal growth factor activates the AKT pathway, which regulates b-catenin translocation. MMP7 and
[52]
CD44, which are b-catenin downstream genes, are involved in macrophage-activated GC cell invasion .
E-cadherin and vimentin expression are markers of EMT. E-cadherin expression in GC cells co-cultured
[53]
with TAMs is decreased, while vimentin expression in GC cells co-cultured with TAMs is increased . Bmi1
is identified as a cancer stem cell marker, and M2 macrophages upregulate Bmi1 expression through miRNA-
[54]
30e* suppression in GC .

Recent studies have revealed the relationship between TAM infiltration and PD-L1 expression. TAM
receptors (Tyro3, Axl and Mertk) upregulate the expression of PD-L1 in a breast cancer cell line. According
to the data, M2 macrophages might activate PD-L1 expression in tumor cells. IFN-g is secreted by
inflammatory cells and is associated with differentiation of macrophages. IFN-g was found to facilitate PD-L1
expression in tumor cells [55,56] . In GC, IFN-g might also influence the relationship between M2 macrophage
infiltration and PD-L1 expression in tumor cells. TAM infiltration is also associated with the upregulation of
[57]
PD-L1 expression in GC cells [Figure 1] .

CANCER ASSOCIATED FIBROBLASTS
Tumor tissues contain cancer cells, other cellular and non-cellular components. The tumor stroma acts as
an essential microenvironment of the cancer cells, which includes many types of non-cancerous cells and
the ECM. Stromal fibroblasts are the major cellular constituents of the tumor stroma and are often called
CAFs. CAFs contribute to the stiffening and remodeling of the stromal ECM, thereby offering an appropriate
field for cancer cell invasion [58,59] . Cancer cells induce the conversion of these various types of cells into