Roles of the tumor microenvironment in the resistance to programmed cell death protein 1 inhibitors in patients with gastric cancer

Table 1 The relationship between immune cells in the tumor microenvironment and the resistance to programmed cell death protein 1 inhibitors in patients with gastric cancer

Types	Functions	Mechanism of PD-1 inhibitor resistance	The potential to reduce PD-1 inhibitor resistance in patients with GC
Cytotoxic T cells	Inhibit and eliminate tumor cells	Decrease the quantity and functionality of CD8+ T cells[6]	New intervention methods to enhance the functionality of cytotoxic T cells
M2 macrophages	Inhibit immune responses, accelerate the growth and proliferation of tumor cells	Release a variety of cytokines that can stimulate tumor cell proliferation, reduce the activity of immune cells[11]	Blocking the Th2-cell cytokines, reducing monocytes to differentiate into M2-type macrophages
Treg cells	Play a significant regulatory role in the low-immunity TME	Suppress the effector T cells’ activity and modulate the response of antitumor T cells[13]	Eliminating Treg cells in GC tissue during PD-1 inhibitor therapy
MDSCs	Participate in chronic inflammation, cancer, and autoimmune diseases	Induce T cell exhaustion and lead T cell to lose immune function and proliferation ability[19]	Blocking CXCR2 could reduce the frequency of PMN-MDSCs and enhance the effectiveness of anti-PD-1
TANs	Promote tumor cell proliferation and exhibiting a tumorigenic effect	Promote tumor progression through the GM-CSF-PD-L1 pathway[27]	Utilizing drugs or other treatment methods to inhibit the activity of these pathological neutrophils or suppress the GM-CSF/PD-L1 immune pathway
Others

PD-1: Programmed cell death protein 1; GC: Gastric cancer; MDSCs: Myeloid-derived suppressor cells; Treg cells: Regulatory T cells; TANs: Tumor-associated neutrophils; TME: Tumor microenvironment; Th2-cell: T helper 2 cell; CXCR2: CXC chemokine receptor 2; PMN-MDSCs: Polymorphonuclear myeloid-derived suppressor cells; GM-CSF: Granulocyte-macrophage colony-stimulating factor; PD-L1: Programmed cell death ligand 1.

Table 2 The relationship between noncellular tumor microenvironment components and the resistance to programmed cell death protein 1 inhibitors in patients with gastric cancer

Types	Functions	Mechanism of PD-1 inhibitor resistance	The potential to reduce PD-1 inhibitor resistance in patients with GC
POSTN	Regulate a variety of biological processes	It can promote the chemotaxis of macrophages indirectly via the Akt signaling pathway, thereby contributing to resistance to PD-1 inhibitor[30,31]	Targeting POSTN+FAP+ eCAFs to reduce resistance to PD-1 inhibitor therapy in GC patients
FAP	An essential factor in the progression of cancer	It can increase proliferation and migration abilities in vitro, enhance tumor growth[34]	Targeting POSTN+FAP+ eCAFs to reduce resistance to PD-1 inhibitor therapy in GC patients
Inflammatory cytokines	Pro-inflammatory and anti-inflammatory effects	GCMSC secretes IL-8 and activates the Akt pathway resulting in the nuclear localization of the key glycolytic enzyme HK2. Phosphorylated HK2 binds to HIF-1α, supporting GC cell proliferation. GCMSC-induced excessive lactate production impairs CD8+ T-cell function[43]	The use of CXCR antagonists and IL-8-neutralizing antibodies can reverse GCMSC-mediated immune suppression, restoring the sensitivity of patients with GC to antitumor effects of PD-1 antibodies
TGF-β	Participate in various physiological processes, including cell growth, differentiation, reproduction, and immune homeostasis	It can promote tumor growth via EMT, genomic instability, angiogenesis, cancer cell activity, immune escape, and metastasis, and create a suitable microenvironment for cancer cell dissemination and further worsening of cancer[46]	Blocking TGF-β could improve anti-PD-1/PD-L1 responses, decrease the tumor phenotype, inhibit tumor development and promote patient outcomes
LPP	Participate in cell cytoskeleton organization, cell movement, and mechanical sensing	High LPP expression was found to correlate with decreased infiltration of resting CD4+ memory T cells and enhanced infiltration of activated CD4+ memory T cells[50]	LPP could be used as a target to forecast the effects of PD-1 inhibitors in patients with GC
Others

GC: Gastric cancer; PD-1: Programmed cell death protein 1; POSTN: Periostin; FAP: Fibroblast activation protein; TGF-β: Transforming growth factor-β; LPP: Lipoma preferred partner; eCAFs: Extracellular matrix cancer-associated fibroblasts; GCMSC: Gastric cancer mesenchymal stem cell; HK2: Hexokinase 2; IL: Interleukin; CXCRs: CXC chemokine receptors; HIF-1α: Hypoxia-inducible factor 1α; EMT: Epithelial-mesenchymal transition; PD-L1: Programmed cell death ligand 1.