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The mechanistic/mammalian target of rapamycin is a downstream mediator in the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, which plays an important role in regulating many cellular functions, including cell growth, proliferation, survival, and metabolic synthesis. Diverse extracellular and intracellular signals in the tumor microenvironment (TME). Dysregulation of the mTOR pathway is frequently reported in many types of human tumors, and targeting the PI3K/Akt/mTOR signaling pathway has been considered an attractive potential therapeutic target in cancer. The PI3K/Akt/mTOR signaling pathway is important not only for cancer development and progression, but also for its critical regulatory role in the tumor microenvironment. Immunologically, mTOR has emerged as a key regulator of immune responses. The mTOR signaling pathway plays an important regulatory role in the differentiation and function of both innate and adaptive immune cells. Given the central role of mTOR in metabolic and translational processes, tumor-associated immune cells influence phenotypic and functional remodeling in the TME. The mTOR-mediated inflammatory response can promote the recruitment of immune cells to the TME, which can exert anti-tumor functions or promote the growth, development and metastasis of cancer cells. Therefore, dysregulated mTOR signaling in cancer may alter the TME, thereby affecting the immune microenvironment of the tumor. Here, we review current knowledge regarding the critical role of the PI3K/Akt/mTOR pathway in regulating and shaping immune responses in the TME.
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Mammalian target of rapamycin (mTOR; now formally known as mechanistic target of rapamycin) is a ubiquitous serine/threonine-specific protein kinase that plays an important role in the regulation of many cellular functions, including cell growth, proliferation, survival, and protein synthesis. . ribosome biogenesis, autophagy, and metabolism (1, 2). mTOR functions in two functionally and structurally distinct multicomponent kinase complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which serve as central nodes of the phosphoinositide 3-kinase (PI3K)/Akt downstream signaling pathway ( 3 ). . The activity of the PI3K/Akt/mTOR pathway is dysregulated in most human tumors and plays an important role in tumorigenesis and cancer progression (4–6). Therefore, targeting the PI3K/Akt/mTOR signaling pathway becomes an attractive potential therapeutic target in cancer (7).
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The tumor microenvironment (TME) consists of benign and malignant cells such as endothelial cells, cancer-associated fibroblasts (CAFs), and several types of tumor-infiltrating immune/inflammatory cells, as well as various soluble factors (cytokines and growth factors). ) is released from subpopulations of cells and plays an important role in facilitating tumorigenesis, promoting tumor growth and the immune system ( 8 ). The TME is rich in immune cells, and reverse signaling between immune cells and cancer cells can reduce the antitumor activity of endogenous tumor-infiltrating immune cells and allow immune evasion (9, 10). Studies have shown that immune responses are closely related to tumor proliferation, angiogenesis, invasion, and metastasis (11). In addition to its important role in cancer, recent studies have established an important regulatory role of mTOR in the differentiation, activation, and functional properties of immune cells, where mTOR functions to coordinate and shape immune effector responses. Therefore, dysfunction of this network can affect the effect of immune cells and influence the nature of the tumor immune microenvironment (TIME) in human cancer (10). As a master regulator of metabolism and translation, mTOR is mainly involved in the central tumor immune microenvironment and influences tumor-associated immune cells for phenotypic and functional reprogramming in the TME. Indeed, mTOR regulates immune responses by regulating immune checkpoint receptors such as interleukin (IL-12), IL-10, transforming growth factor (TGF-β) and tumor necrosis factor (TNF). cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed death 1 (PD-1) (12, 14). In addition, a recent study has shown that mTOR gene expression is significantly associated with various immune cells and immunosuppressive drugs in patients with clear cell renal cell carcinoma (CCRCC) (15). The mTOR-mediated inflammatory response promotes the recruitment of immune cells to the TME via inflammatory mediators, which can exert antitumor functions or promote the growth, proliferation, and invasiveness of cancer cells (14).
This review focuses on current knowledge regarding the central role of the mTOR signaling pathway in regulating and shaping immune responses in the TME.
MTOR is an unusual serine/threonine-specific protein kinase that belongs to the phosphatidylinositol-3 kinase-related kinase (PIKK) family ( 16 ). mTOR acts as a downstream effector of the PI3K/Akt signaling pathway through two distinct intracellular complexes, mTORC1 and mTORC2 ( 3 ). Both complexes contain three conserved subunits: mTOR, the catalytic subunit, the DEP-containing mTOR interacting protein (DEPTOR), and the mammalian SEC13 protein 8/G protein β subunit-like (mLST8/GβL). In addition to homologous subunits, the regulatory-associated protein of mTOR (RAPTOR) and the proline-rich Akt substrate 40 kDa (PRAS40) protein are unique subunits of the mTORC1 complex, while the rapamycin-sensitive protein of mTOR (RICTOR) is found. With Richter. (Protor) and mammalian stress-activated protein kinase (SAPK)-interacting protein 1 (mSIN1) are specific components of the mTORC2 complex (Figure 1) (16). The mTOR pathway senses various intracellular and extracellular signals in the form of growth factors, cytokines, nutrients and energy levels in ATP, cellular stress and inflammation. The downstream signaling inputs of these various signals are primarily on the PI3K/Akt pathway, which ultimately activates mTOR (Figure 1) (1, 12). Phosphatase and tensin homolog (PTEN), a well-known tumor suppressor, negatively regulates the PI3K/Akt/mTOR signaling pathway. In many cancer types, PTEN dysregulation or PTEN loss-of-function mutations result in altered PI3K/Akt/mTOR signaling that contributes to tumorigenesis ( 17 ). The tuberous sclerosis complex (TSC) is a major upstream negative regulator of mTORC1 kinase activity, which exists in a heterodimer consisting of TSC1 and TSC2 (also known as hermetin and tuberin, respectively). TSC2 acts as a GTPase-activating protein (GAP) that inhibits the activity of a RAS homologue enriched in the brain (Rheb), an essential activator of mTORC1 ( 18 ). Activation of RAS-MAPK (mitogen-activated protein kinase) and PI3K/Akt signaling leads to inhibitory phosphorylation of TSC2 and dissociation of the TSC1/TSC2 complex, leading to activation of mTORC1 signaling through Rheb. Thus, suppression of TSC allows GTP-bound Rheb to bind and activate mTORC1 ( Fig. 1 ) ( 19 , 20 ). Under normal conditions, mTORC1 activation stimulates protein synthesis essential for cell growth and proliferation, particularly ribosomal protein S6 kinases (S6Ks) and eukaryotic translation initiation factor (eIF4E)-binding proteins (4E-BPs) (20, 21). Phosphorylated S6K1 promotes mRNA translation and cell growth through ribosomal S6 and eIF-4B phosphorylation. mTOR-dependent phosphorylation of 4E-BP1 can disrupt its binding to eIF4E, which induces translation (12,21). mTOR signaling regulates several transcription factors such as c-MYC, hypoxia-inducible factor 1-α (HIF1-α), STAT3, transcription factor EB (TFEB), peroxisome proliferator-activated receptor-γ (PPARγ), PPARA and it moves. It , and sterol regulatory element-binding proteins (SREBPs) (22). Also, mTORC1-mediated inhibition of autophagy, specifically by the serine/threonine kinase Unc-51-like kinase 1 (ULK1), is an essential component of autophagy phosphorylation, which requires S6Ks (S6K1 and S6K2) and 4E-BP1. for cell growth (23). In addn., phosphorylation of PRAS40
In mTORC1, an inhibitor of mTORC1, PRAS40, causes its dissociation from mTORC1 and its binding to 14-3-3 proteins leads to indirect activation of mTORC1 independent of TSC1/2 (24).
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Figure 1 PI3K/Akt/mTOR signaling pathway and mTORC1 and mTORC2 signaling pathways. Schematic representation of the molecular components and signaling pathways associated with the PI3K/Akt/mTOR signaling pathway and its major downstream effectors. Depicts the key molecular factors and signaling pathways seen by mTORC1 and mTORC2 and the processes that regulate key cellular events including growth, protein synthesis, metabolism, survival, and proliferation. mTOR, mechanistic target of rapamycin; PI3K, phosphoinositide 3 kinase; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; RAPTOR, regulatory-associated protein of mTOR; RICTOR, a rapamycin-inducible mTOR partner; mSIN1, mammalian stress-activated protein kinase interacting protein; eIF4E, eukaryotic initiation factor 4E; 4EBP1, eIF4E-binding protein 1; S6K1, S6 kinase 1; HIF-1α, Hypoxia Inducible Factor 1α; PKC, protein kinase C; AMPK, AMP activated protein kinase; SGK1, glucocorticoid regulated kinase 1; FKBP12, FK506 binding protein 12; LKB1, liver kinase B1; DEPTOR, DEP-containing mTOR interacting protein; mLST8, mammalian killer with Sec13 protein; RAPTOR, regulatory-associated protein of mTOR; PRAS40, proline-rich AKT substrate 40 kDa; mSin1, mammalian stress-activated protein kinase (SAPK)-interacting protein 1; Rheb, RAs homologue enriched in brain; TSC, tuberous sclerosis complex; GSK3, Glycogen synthase kinase-3; PDK1, phosphoinositide-dependent kinase 1; FOXO3, forkhead box family transcription factor 3; PTEN, phosphatase and tensin homologue; REDD1, regulated in development and DNA damage response 1.
Rapamycin (Sirolimus) is a macrolide compound produced by a strain of Streptomyces hygroscopicus and was first found to have potent and selective antifungal activity in soil samples collected from Rapa Nui (Easter Island) (25). Subsequently, rapamycin and its analogs everolimus (RAD001), temsirolimus (TRM-986), ridaforolimus (AP23573, MK-8669), and zotarolimus (ABT-578) were found to have both immunosuppressive and antitumor potential. It has emerged as a promising class of new antitumor agents (5, 26). Rapamycin binds to the cytoplasmic receptor FK506 binding protein 12 (FKBP12), and this complex associates with the FKBP12-rapamycin-binding (FRB) domain.
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