Stat (signal transducer and activator of transcription) protein family, as a key signal transduction hub in cells, includes seven members: STAT1-4, STAT5a, STAT5b and STAT6, and plays a complex regulatory role in the occurrence and development of malignant tumors. Recent studies have confirmed that STAT protein forms a precise regulatory network in key biological processes such as tumor proliferation, metabolic reprogramming and immune escape by integrating extracellular signals and gene transcription regulation. This paper systematically expounds the multi-dimensional mechanism of STAT protein in tumor microenvironment and discusses its clinical transformation potential.
First, the tumor regulatory duality of STAT signaling pathway
(I) Biological characteristics of tumor promotion
1. Abnormal cell cycle regulation
STAT protein regulates the expression of key cell cycle regulators by directly binding to the promoter region of the target gene. STAT3/STAT5 can specifically activate G1/S phase transition related genes such as Cyclin D1 and c-Myc, and promote the activity of cyclin-dependent kinase (CDK). Studies have shown that the continuous activation of STAT3 can relieve the inhibition of retinoblastoma protein (Rb) on E2F transcription factor and accelerate the cell cycle process. At the same time, STAT5 synergistically enhanced the proliferation-promoting effect of CDK-Rb-E2F signal axis by up-regulating the expression of CDK4/6.
2. Mechanism of apoptosis resistance
STAT-mediated anti-apoptosis effect involves dual regulatory pathways of mitochondria and death receptors. STAT3/STAT5 can activate anti-apoptosis members of Bcl-2 family (Bcl-2, Bcl-xL, Mcl-1) and inhibit the expression of pro-apoptosis proteins such as Bax and Bak. In the death receptor pathway, STAT3 reduces the activation efficiency of caspase-8 by inhibiting the expression of Fas ligand. STAT5 can also directly interact with Bcl-xL in a transcription-independent way, and enhance its mitochondrial membrane stability.
3. Maintenance of tumor stem cell characteristics
STAT signal maintains the characteristics of tumor stem cells by regulating the core dry transcription factor network (Oct4/Sox2/Nanog). STAT3 forms a positive feedback loop with Wnt/β-catenin pathway, which promotes the expression of stem cell markers such as Lgr5. Experiments confirmed that STAT5 phosphorylation can induce the expression of Notch signaling ligand Jagged1 and enhance the self-renewal ability of tumor cells. In addition, STAT3 maintains DNA hypomethylation through epigenetic regulation mechanism and promotes the continuous activation of stem cell-related genes.
4. Shaping the immunosuppressive microenvironment
STAT3/STAT5 plays a key role in tumor immunoediting. It promotes the expansion of regulatory T cells (Treg) and inhibits the function of cytotoxic T lymphocytes (CTL) by inducing the expression of immune checkpoint molecules such as PD-L1 and IDO1. In myeloid cells, STAT3 activation drives the polarization of M2-type macrophages and the recruitment of MDSCs, and establishes immune-immune microenvironment through the metabolic inhibition mechanism mediated by arginase -1(ARG1) and nitric oxide synthase (iNOS).
(II) Characteristics of tumor inhibitory function
STAT1, as the core effector molecule of interferon signal, induces anti-tumor immune response by activating IRF1, CXCL10 and other genes. Up-regulation of MHC class I molecule expression mediated by STAT1 can enhance the efficiency of tumor antigen presentation and promote CTL killing function by activating granzyme B pathway. STAT1 and STAT3 are in dynamic balance in tumor microenvironment, and their phosphorylation level ratio (p-STAT1/p-STAT3) can be used as an important biomarker for prognosis evaluation.
Second, STAT-mediated tumor metabolism reprogramming network
(I) Regulation of glucose metabolism
STAT protein drives Warburg effect through multiple mechanisms: ① transcription up-regulates GLUT1/3 to enhance glucose uptake; ② Phosphorylation activates HK2 to maintain hexokinase activity; ③ Regulating the transformation of PKM2 subtype affects the metabolic flow of pyruvate. Studies have shown that STAT3 and HIF-1α synergistically induce the expression of LDHA, promote lactic acid production and microenvironment acidification. PKM2 can be used as tyrosine phosphorylated kinase of STAT3, forming a positive feedback loop of metabolism-signal transduction.
(II) Lipid metabolism remodeling
STAT signal regulates lipid homeostasis through the following ways: ① Transcriptional activation of SREBP1c promotes the expression of lipid synthase such as FASN and ACC; ② Up-regulating CD36-mediated exogenous lipid uptake; ③ Activate CPT1A to enhance fatty acid β-oxidation. In the metastatic microenvironment, STAT3 promotes the formation of lipid droplets by inducing the expression of FABP4, which provides energy for tumor cells to migrate. The latest research reveals that STAT5 can enhance cholesterol biosynthesis and maintain cell membrane fluidity through mTORC1-S6K pathway.
(III) Regulation of Glutamine Metabolism
STAT3 drives glutamine addiction through the following mechanisms: ① synergistic up-regulation of ASCT2(SLC1A5) expression with c-Myc; ② Activating glutaminase (GLS) to promote glutamine decomposition; ③ Regulating glutathione synthesis to maintain redox steady state. STAT5 promotes purine biosynthesis and supports the rapid proliferation of tumor cells by activating ATIC gene under the condition of nutrient deficiency. STAT6 was found to affect α-KG production by regulating glutamate dehydrogenase (GLUD) activity, and epigenetically modify tumor metabolic phenotype.
Third, the regulatory role of STAT signal in tumor immune metabolism
(I) Reprogramming of immune cell metabolism
STAT3 reshapes the immune metabolism landscape through the following ways: ① inhibiting the glycolysis of CD8+T cells, enhancing FAO and promoting the formation of depletion phenotype; ② Inducing glutamine catabolism in Treg cells to maintain immunosuppression; ③ ARG1 regulates urea cycle of macrophages and promotes M2 polarization. On the contrary, STAT1 activation can enhance the metabolism of OXPHOS in DC cells and promote the efficiency of antigen cross-presentation. Recent studies have found that STAT5 affects the immunosuppressive activity of MDSCs by regulating NAD+ metabolism, which provides a new target for combined therapy.
(II) Dynamic control of immune checkpoints
STAT3 has a direct regulatory relationship with PD-L1 expression: ① binding to the -1586/-1578 site of PD-L1 promoter region directly activates transcription; ② Indirect expression was induced by IL-6-JAK-STAT3 axis. STAT5 was found to regulate the expression of TIM-3, and its co-expression pattern with LAG-3 affected the process of T cell failure. STAT6 participates in immune escape by regulating the expression of CD276(B7-H3), suggesting that different STAT subtypes have unique checkpoint regulation characteristics.
Fourth, the precise treatment strategy of targeting STAT pathway
(I) Development of small molecule inhibitors
1. Tyrosine phosphorylation inhibitor: compounds such as WP1066 and Stattic inhibit STAT activity by blocking the dimerization of SH2 domain.
2. DNA binding inhibitor: Platinum derivatives can competitively bind to the DNA binding domain of STAT3.
3. Epigenetic regulator: JAK/HDAC double inhibitors can synergistically inhibit STAT signal transduction.
(II) Targeted nucleic acid therapy
1. Antisense oligonucleotide: ASON targeting STAT3 mRNA can specifically down-regulate protein expression.
2. siRNA nano-delivery system: pH-responsive nanoparticles achieve tumor site-specific gene silencing.
3. CRISPR/Cas9 gene editing: Construction of STAT3/STAT5 double knockout CAR-T cells to enhance anti-tumor activity.
(III) Combination therapy strategy
1. Immune checkpoint blocking synergy: STAT3 inhibitor combined with anti-PD-1 antibody can reverse T cell depletion.
2. Synergy of metabolic intervention: LDHA inhibitor combined with STAT5 blocker can enhance oxidative stress.
3. radiosensitization strategy: STAT3 inhibition enhances radiosensitivity by down-regulating Bcl-xL.
Fifth, summary
Although STAT targeted therapy has made remarkable progress, it still faces many challenges: ① the analysis of tissue-specific regulation mechanism is insufficient; ② In-depth exploration of functional heterogeneity of ②STAT subtypes; ③ The effect of dynamic change of microenvironment on the response to treatment. In the future, it may be necessary to integrate cutting-edge technologies such as single cell sequencing and spatial metabonomics, draw the spatio-temporal dynamic map of STAT signal network, and develop subtype selective inhibitors and dual STAT/ metabolic targeted drugs, which may become an important research direction.
Disclaimer: This article is only for the purpose of knowledge exchange and sharing and popular science, and does not involve commercial propaganda, and is not used as relevant medical guidance or medication advice. If the article is infringing, please contact to delete it.
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