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Critical Reviews in Oncology / Hematology
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CRITICAL REVIEWS in Oncology Hematology
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Death receptor 3: A paradoxical biomarker and therapeutic target in pan-cancer
Wenxuan Fang a,b,1, Junfang Duc,1, Zedong Xuª, Qiuyu Liua,b, Yonghong Liub,”, Xueni Wang a, İD **
ª Guangxi Engineering Research Center for High-Value Utilization of Guangxi-Produced Authentic medicinal Herbs, Institute of Traditional Chinese and Zhuang-Yao Ethnic Medicine, Guangxi University of Chinese Medicine, Nanning 530200, China
b Guangxi key laboratory of marine drugs, Institute of marine drugs, Guangxi University of Chinese Medicine, Nanning 530200, China ” School of Yao Medicine, Guangxi University of Chinese Medicine, 179 Mingxiudong Road, Xixiangtang District, Nanning 530001, China
ARTICLE INFO
Keywords:
Death receptor 3 Cancer Apoptosis Necroptosis Angiogenesis Anti-tumor immunity
ABSTRACT
Death receptor 3 (DR3/TNFRSF25) is a member of the tumor necrosis factor receptor superfamily, exhibiting dual roles in regulating tumor apoptosis and metastasis. Through literature review and pan-cancer analysis, this study reveals that DR3 expression exhibits distinct tumor type specificity: it is highly expressed in seven cancers, including Bladder Urothelial Carcinoma (BLCA), while showing low expression in sixteen cancers, such as Adrenocortical carcinoma (ACC). Its expression correlates with CD8+ T cell and natural killer (NK) cell infil- tration, tumor mutational burden (TMB), and is closely associated with prognosis, exhibiting opposite trends across different cancer types. Mechanistically, DR3 activates apoptosis or programmed necrosis pathways by binding its ligand TL1A. Its interaction with NF-KB exhibits directional discrepancies across cancer types, which differentially regulate cell death. Additionally, DR3 suppresses angiogenesis and modulates antitumor immune responses. While multiple natural and synthetic compounds modulate DR3-related pathways to exert antitumor effects, no direct-targeting drugs are currently available. The presence of DR3 isoforms and decoy receptor DcR3 adds complexity to its signaling, suggesting that future clinical applications require precise evaluation consid- ering the tumor microenvironment. In summary, DR3 is a multifunctional molecule with significant potential as a biomarker and therapeutic target. However, its duality and context-dependent effects necessitate the develop- ment of personalized strategies based on tumor molecular subtyping.
1. Introduction
Despite the rapid development of targeted cancer therapies, drug resistance and metastatic spread of tumors remain major clinical chal- lenges (Jin et al., 2023). The death receptor family has become an emerging therapeutic target due to its direct activation of exogenous apoptotic pathways, among which death receptor 3 (DR3/TNFRSF25), as a member of the TNF receptor superfamily, has attracted widespread attention due to its dual paradoxical roles in pro-apoptosis and pro-metastasis.
DR3, a member of the tumor necrosis factor receptor superfamily (TNFR), is a type I transmembrane protein (molecular weight
approximately 47 kDa) consisting of 417 amino acids, with an extra- cellular region containing a cysteine-rich structural domain (CRD) and an intracellular region with a death domain (DD) (Kitson et al., 1996). DR3 plays a central role in the regulation of adaptive immunity, espe- cially in T cell (e.g., Th17 and Treg cells) activation, proliferation, dif- ferentiation, and cytokine production, and is involved in the maintenance of immune homeostasis. Its abnormal signaling is closely associated with various inflammatory and autoimmune diseases, such as asthma, acute respiratory distress syndrome, rheumatoid arthritis, and inflammatory bowel disease, and is therefore regarded as a significant potential therapeutic target (Meylan et al., 2011; Sheikh and Huang, 2004; D. Zhang et al., 2022; Zhang et al., 2023; J. Zhang et al., 2022).
* Corresponding author.
** Corresponding author at: Guangxi Engineering Research Center for High-Value Utilization of Guangxi-Produced Authentic medicinal Herbs, Institute of Traditional Chinese and Zhuang-Yao Ethnic Medicine, Guangxi University of Chinese Medicine, Nanning 530200, China. E-mail addresses: yonghongliu@scsio.ac.cn (Y. Liu), wangxueni@gxtcmu.edu.cn (X. Wang).
1 These authors contributed equally to this work
https://doi.org/10.1016/j.critrevonc.2026.105157
Tumor Necrosis Factor-like Ligand 1 A (TL1A) is the sole known ligand for DR3. It is primarily expressed by activated T cells, macro- phages, dendritic cells, endothelial cells, and, under certain conditions, epithelial cells and fibroblasts. These cells are widely present within the tumor microenvironment, suggesting that the TL1A/DR3 signaling pathway may play a role in tumor immunity (Bamias et al., 2025; Bittner et al., 2016; Xu et al., 2022). DR3 binds to its ligand TL1A via its extracellular domain, subsequently activating the FADD/caspase-8 apoptotic cascade through its intracellular death domain, thereby inducing apoptosis in tumor cells, and also strongly triggers necroptotic apoptotic cell death or activation of anti-tumor immune responses (e.g., enhancement of effector T-cell activity, suppression of regulatory T-cell function) in immune cells (Bittner et al., 2017; Liman et al., 2024; Luo et al., 2023; Qi et al., 2018). However, in colorectal cancer and hepa- tocellular carcinoma, the splice variants (SV2/SV3) generated by exon 10 deletion activate the NF-KB-MMP9 pathway to promote invasion and metastasis, and even antagonize the oncogenic function of p53, which results in the unique phenomenon of “DR3 paradox” (Ge et al., 2013; Gout et al., 2006; Murtaza et al., 2009; Zhang et al., 2015).
Understanding the complex mechanism of the DR3 signaling pathway can help develop targeted cancer therapeutic strategies.
This study was based on PubMed and Web of Science databases to retrieve the literature up to March 15, 2025, and a systematic search was performed using the dual strategy of “(Cancer [Title]) AND (DR3 [Title])” and “(Cancer) AND (Death Receptor 3)“. The initial screening of titles/abstracts and full-text assessment included 26 studies that met the criteria. The analysis showed that the available evidence focused on the anti-cancer effects of DR3 through mediating apoptosis, inhibiting angiogenesis, and enhancing immune surveillance. Notably, the re- ported active compounds mainly activate the signaling pathway of DR3 by up-regulating its expression rather than direct receptor binding, which in turn induces tumor-suppressive effects. In this review, the molecular mechanism of DR3 is systematically reviewed, and its trans- lational potential as a novel anticancer therapeutic target is explored based on the existing research results.
A
Group
Tumor N
Normal
B
TNFRSF25 Expression
8
ns
ns
ns
ns
ns
ns
TNFRSF25 Expression
ns
ns
**
ns
6
6
4
4
2
2
0
0
L
ACC(T=79;N=0)
BLCA(T=406;N=19)
BRCA(T=1101;N=113)
CESC(T=306;N=3)
CHOL(T=35;N=9)
COAD(T=455;N=41)
DLBC(T=48;N=0)
ESCA(T=163;N=11)
GBM(T=153;N=5)
HNSC(T=504;N=44)
KICH(T=65;N=25)
KIRC(T=532;N=72)
KIRP(T=290;N=32)
LAML(T=150;N=0)
LGG(T=513;N=0)
LIHC(T=371;N=50)
LUAD(T=516;N=59)
LUSC(T=501;N=49)
MESO(T=87;N=0)
OV(T=376;N=0)
PAAD(T=179;N=4)
PCPG(T=181;N=3)
TNFRSF25 Expression
Group
Tumor
Normal
TNFRSF25 Expression
9
ns
ns
ns
ns
**
9
6
6
3
3
0
0
ACC
BLCA
BRCA
CESC
CHOL
COAD
DLBC
ESCA
GBM
HNSC
KICH
KIRC
KIRP
LAML
LGG
LIHC
LUAD
LUSC
MESO
OV
PAAD
PCPG
*
ns
*
**
ns
*
ns
TNFRSF25 Expression
7.5
5.0
2.5
0.0
PRAD
READ
SARC
SKCM
STAD
TGCT
THCA
THYM
UCEC
UCS
UVM
2. Pan-cancer analysis of DR3
2.1. The expression of DR3 in different cancer tissues
To evaluate the potential diagnostic value of DR3 in cancer, we systematically analyzed the differences in the expression of DR3 in various tumor tissues and normal tissues based on the TCGA database and its clinical information. The results showed that DR3 was signifi- cantly upregulated in seven cancers, including Bladder Urothelial Car- cinoma (BLCA), Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), Cholangiocarcinoma (CHOL), Head and Neck squamous cell carcinoma (HNSC), Kidney renal clear cell carcinoma (KIRC), Liver hepatocellular carcinoma (LIHC), and Pheochromocytoma and Paraganglioma (PCPG), while expression was significantly down- regulated in Kidney Chromophobe (KICH) (Fig 1A, B). Given the limited number of normal samples in TCGA, this study further integrated normal tissue data from the GTEx (Genotype-Tissue Expression) database to expand the scope of comparison. The results showed that, in addition to the seven cancers mentioned above, DR3 expression was up-regulated in Pancreatic adenocarcinoma (PAAD) and Stomach adenocarcinoma (STAD), and Testicular Germ Cell Tumors (TGCT), while it was down- regulated in 16 cancers, these include Adrenocortical carcinoma (ACC), Breast invasive carcinoma (BRCA), Glioblastoma multiforme (GBM), Kidney renal papillary cell carcinoma (KIRP), Brain Lower Grade Glioma (LGG), Ovarian serous cystadenocarcinoma (OV), Prostate adenocarcinoma (PRAD), Rectum adenocarcinoma (READ), Skin Cuta- neous Melanoma (SKCM), Thyroid carcinoma (THCA), Uterine Corpus Endometrial Carcinoma (UCEC) and Uterine Carcinosarcoma (UCS). However, the expression of DR3 in four tumors, Colon adenocarcinoma (COAD), Esophageal carcinoma (ESCA), Lung adenocarcinoma (LUAD), and Lung squamous cell carcinoma (LUSC), was unclear (Fig 1C, D, E).
2.2. Correlation of DR3 expression with immune infiltration
Tumor Microenvironment (TME) is important for tumor develop- ment and prognosis assessment. In this study, we systematically assessed the association between DR3 expression and immune cell infiltration using six algorithms (TIMER, xCell, MCP-counter, CIBERSORT, EPIC, and quanTIseq) integrated with the R package immunedeconv. The re- sults showed that in most cancers, DR3 expression was significantly and positively correlated with CD8+ T cell, CD4+ T cell, natural killer (NK) cell, endothelial cell, and B cell infiltration, and negatively correlated with infiltration of uncharacterized cells, macrophages, and lymphoid progenitor cells (Fig. 2).
2.3. Association of DR3 expression and genomic heterogeneity
Tumor Mutational Burden (TMB) is an important predictor of immunotherapy efficacy. In this study, we further investigated the relationship between DR3 expression and TMB and found that signifi- cantly positively correlated with TMB in Stomach adenocarcinoma (STAD) and Lung adenocarcinoma (LUAD), while significantly nega- tively correlated with TMB in Breast invasive carcinoma (BRCA), Pros- tate adenocarcinoma (PRAD), Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (DLBC) and Liver hepatocellular carcinoma (LIHC) (Fig. 3).
2.4. Correlation between DR3 expression and cancer survival prognosis
Cox proportional risk regression analysis revealed that high expres- sion of DR3 was an independent risk factor in Adrenocortical carcinoma (ACC), Colon adenocarcinoma (COAD), Kidney renal clear cell carci- noma (KIRC) and Mesothelioma (MESO) were independent risk factors (HR >1, P < 0.05), suggesting that they were significantly associated with poor prognosis, while in Head and Neck squamous cell carcinoma (HNSC) and Skin Cutaneous Melanoma (SKCM), high DR3 expression was a protective factor (HR <1, P < 0.05), predicting prolonged patient
survival(Fig. 4A). Kaplan-Meier survival curve analysis further validated that high DR3 expression was a risk factor in Thymoma (THYM) and a protective factor in Breast invasive carcinoma (BRCA) (log-rank P < 0.05) (Fig. 4B).
2.5. The mechanism of action of DR3 in regulating cell death
The mechanism and clinical value of the DR3 signaling pathway in tumor therapy have been gradually elucidated. Studies have shown that binding of DR3 to the ligand TL1A can effectively inhibit cancer cell proliferation and induce apoptosis. Cavallini’s team first found the phenomenon of abnormally high expression of DR3 in early-stage chronic lymphocytic leukemia (CLL) patients in 2015 and demon- strated that exogenous TL1A could play a role in inhibiting B-cell re- ceptor stimulation-mediated cell proliferation in CLL cells (Cavallini et al., 2015). The 2018 study further found that anti-mitotic chemo- therapeutic agents (e.g., paclitaxel and vincristine) trigger lysosomal secretion of TL1A by inducing mitotic arrest, and that TL1A binds to DR3 and activates the FADD/Caspase-8-dependent death-inducing signaling complex (DISC), which then drives apoptosis of colorectal cancer cells, and the strength of its effect is correlated with the expression of DR3/TL1A (Qi et al., 2018). Notably, in addition to mediating apoptosis, DR3 can trigger TL1A-induced necroptosis by activating the RIP1/- RIP3/MLKL signaling pathway in studies of cervical cancer, colon can- cer and leukemia, which is accompanied by, but not dependent on, the generation of reactive oxygen species, thus establishing DR3 as a new type of necroptosis-inducing receptor and suggesting that this pathway can be used as an important biomarker for the prediction of chemo- therapeutic efficacy (Bittner et al., 2017).
The interaction of DR3 with the nuclear factor-KB (NF-KB) signaling axis plays a key role in regulating apoptosis and overcoming therapeutic resistance in tumor cells, and is an important target for anticancer drug discovery. However, there are significant contradictory findings regarding the specific direction of modulating DR3 expression (up- or down-regulation) to synergistically inhibit NF-KB to induce apoptosis. In 2009, Murtaza et al. found that in pancreatic cancer (PaC), DR3 is involved in the constitutive activation of NF-KB and suppresses the NF- KB signaling pathway by down-regulating the expression of the death receptor DR3. This leads to the induction of apoptosis and inhibition of invasion in pancreatic cancer cells (Murtaza et al., 2009). In the same year, Zhang L et al. found that specific inhibition of DR3 expression significantly inhibited the proliferation and induced apoptosis of hepa- tocellular carcinoma SMMC7721 cells (Zhang et al., 2009). Paradoxi- cally, subsequent studies have concluded the opposite direction of DR3 regulation: in 2014, a study by Choi KE’s team confirmed that enhancing DR3/DR6 expression and inhibiting the NF-KB pathway was equally effective in inducing apoptosis in lung cancer cells (A549 and NCI-H460) (Choi et al., 2014). Particularly noteworthy, the 2016 study by Lee HL et al. further expanded the application of this strategy through ex vivo experiments: they found that synergistic enhancement of DR3/DR5 expression and dual blockade of NF-KB activation significantly inhibited the proliferation of cancer cells in cervical cancer cells; what’s more, in the case of TRAIL (TNF-related apoptosis-inducing ligand) resistant cancer cells (such as A549 and MCF-7), drug resistance was effectively reversed by down-regulating NF-KB activity while up-regulating DR3/DR5 expression, which enhanced the sensitivity of cancer cells to chemotherapy (Lee et al., 2016). Thus, despite the general support for the central idea of targeting the DR3/NF-KB axis to induce apoptosis and overcome drug resistance, studies after 2009 vs. 2014 present a remarkable contradiction regarding the optimal direction of DR3 expression regulation (up- vs. down-regulation) required to achieve synergistic pro-apoptotic effects. Together, these seemingly opposing results reveal the complexity of this signaling network, strongly sug- gesting that the role of DR3 signaling is highly context-specific and that its dual roles need to be carefully assessed before clinical application (Fig. 5).
| CIBERSORT | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| T | cell regulatory (Tregs) | *** | . | ... | · p<0.05 | |||||||||||
| T cell gamma delta T cell follicular helper T cell CD8+ | *** *** ... | ** p < 0.01 ... *** p<0.001 | ||||||||||||||
| T cell CD4+ naive | 0.50 | |||||||||||||||
| T cell CD4+ memory resting T cell CD4+ memory activated | ... | 0.25 0.00 | ||||||||||||||
| Neutrophil NK cell resting NK cell activated | ... | |||||||||||||||
| Myeloid Myeloid | dendritic cell resting dendritic cell activated Monocyte Mast cell resting Mast cell activated | .. | *** | *** | ** | |||||||||||
| Macrophage M2 Macrophage M1 Macrophage MO Eosinophil | . | . | ... *** | .. *** | . | ... | ... | . | ||||||||
| B cell plasma B cell naive | *** | . | ** | *** | *** *** *** *** | *** | *** ** . *** | |||||||||
| B cell memory | ACC BLCA BRCA | CESC | .. CHOL | COAD | ... DLBC ESCA | GBM ANSC KICH KIRC | KIRP KIRC KIRP | LAML LGG . - · LAML | LIHC LUAD EPIC | *** LUSC | MESO OV | *** PAAD PCPG PRAD READ | *** SARC SKCM | STAD TGCT ... ... SKCM STAD | THCA THYM UCEC UCS UVM . *** ** | |
| uncharacterized cell T cell CD8+ T cell CD4+ NK cell Macrophage Endothelial cell B cell | ... ... ACC BLCA BRCA | *** ... *** . . CESC | *** *** + *** CHOL | COAD | ... ... *** DLBC ESCA | *** . ... GBM HNSC KICH | MCPCOUNTER *** · . . ... LGG LIHC | *** LUAD | LUSC . MESO | . ** ... . . *** OV PAAD PCPG PRAD | SARC READ | *** ... ** . . . *** TGCT THCA THYM UCEC UCS UVM | ||||
| cytotoxicity score | * | ¥ | .** | · ... | *** | . | ||||||||||
| T cell CD8+ | *** | ... | *** | + | *** | *** | ||||||||||
| T cell | *** ** *** | *** | + | *** | *** | *** | *** ... *** | *** *** | *** | *** | ||||||
| Neutrophil | . | . *** | *** | * | ||||||||||||
| NK cell | *** | *** | *** | .** | *** . | . | *** | *** | *** | |||||||
| Myeloid dendritic cell | *** | *** | ... | |||||||||||||
| Monocyte | ... | . | ||||||||||||||
| Macrophage/Monocyte | ... | ... | ... ... | . | ||||||||||||
| Endothelial cell | ... | . | .44 | ... | . | . | ||||||||||
| B cell | ACC BLCA BRCA | CESC | CHOL | COAD | DLBC ESCA | GBM HNSC KICH | KIRC KIRP | LAML | . LGG LIHC QUANTISEQ | LUAD | LUSC - MESO | OV PAAD PCPG PRAD | READ SARC | SKCM *** STAD | TGCT . THCA THYM UCEC UCS UVM | |
| uncharacterized cell | . | . * .. | .. | .. | ||||||||||||
| T | cell regulatory (Tregs) | ... | ... | ... | - | ... | . . | |||||||||
| T cell CD8+ | . *** | ... | ... | ... | ** | ... | ... ... | |||||||||
| T cell | CD4+ (non-regulatory) | . | .. | . | . | ... | ||||||||||
| Neutrophil | . | ... | . | |||||||||||||
| NK cell | . *** | *** *** | . | ... | ||||||||||||
| Myeloid dendritic cell | ... | ** | . | ... | . | |||||||||||
| Monocyte | . | ... | ... | ... | .** | |||||||||||
| Macrophage M2 | *** | . | . | *** | *** | . | . | . | ||||||||
| Macrophage M1 | ** | - ** | ||||||||||||||
| B cell | *** | * | *** | *** ** | *** | *** *** | ||||||||||
| ACC BLCA BRCA | CESC | CHOL | COAD | DLBC ESCA | GBM HNSC KICH KIRC | KIRP | LAML LGG | LIHC LUAD TIMER | LUSC | MESO OV | PAAD PCPG PRAD READ | SARC SKCM | STAD TGCT | THCA THYM UCEC UCS UVM | ||
| T cell CD8+ T cell CD4+ | *** . | *** ... | .** | . ... | . *** ... | ... | *** | .** | *** .** | ... | ... | *** ... | *** | ** . ... | ||
| Neutrophil Myeloid dendritic cell Macrophage | .. | .** | ... | . ... *** | . *** | *** | *** *** *** .** *** | . * *** | . . ** | *** *** | . . *** *** *** ... ** | |||||
| B cell | ACC BLCA BRCA | CESC | CHOL | COAD | DLBC | ESCA + GBM HNSC KICH | KIRC | KIRP | LGG LIHC LUAD | XCELL LUSC | . MESO | OV PAAD PCPG PRAD | READ *** SARC | SKCM STAD | . TGCT THCA THYM UCEC UCS UVM | |
| stroma microenvironment | score score | ** | ||||||||||||||
| immune T cell regulatory (Tregs) T cell gamma T cell T cell CD8+ | score delta NK naive | |||||||||||||||
| T cell T | CD8+ effector memory cell CD8+ central memory cell CD8+ T cell CD4+ naive | |||||||||||||||
| T cell T | T cell CD4+ memory CD4+ effector memory cell CD4+ central memory I T cell CD4+ | Th2 Th1 .. | ||||||||||||||
| T cell Myeloid | CD4+ (non-regulatory) dendritic cell activated Plasmacytoid dendritic Neutrophil NK Myeloid dendritic | cell cell cell | ||||||||||||||
| Monocyte Mast Macrophage Macrophage Macrophage Hematopoietic stem | cell M2 M1 cell | |||||||||||||||
| Granulocyte-monocyte progenitor Common myeloid progenitor Eosinophil Endothelial | cell | |||||||||||||||
| Common lymphoid progenitor Class-switched memory B B cell plasma | cell | |||||||||||||||
| B cell naive B cell memory | ||||||||||||||||
| B | cell | |||||||||||||||
Correlation
0.25
ACC BLCA
BRCA
CESC
CHOL
COAD
DLBC
ESCA
GBM
HNSC
KICH
KIRC
KIRP
LAML
LGG
LIHC
LUAD
LUSC
MESO
OV
PAAD
PCPG
PRAD
READ SARC
SKCM
STAD
TGCT
THCA
THYM
UCEC
UCS
UVM
(caption on next page)
CESC
0.
74
READ
0.1
61
STAD
0.1
54
ESCA
0.
53
ACC
0.
46
LUAD
0.
43
THYM
0.
13
LAML
0.
09
PCPG
0.08
HNSC
0.0
74
LUSC
0.0
39
LGG
D.C
17
TGCT
.0
16
BLCA
0
.C
14
PAAD
0.002
KIRC
0
0 4
KIRP
0.
0
5
SKCM
-0.
025
OV
-0. 028
KICH
0.
034
UCEC
-0.049
THCA
0.
076
GBM
0.
089
COAD
0
094
BRCA
0.
096
MESO
0.
115
CHOL
0.
118
LIHC
0.
121
UCS
0.
32
SARC
0.
38
PRAD
0.
42
UVM-
0.
61
DLBC
0.
534
-0.4
0.2
0.0
0.2
Correlation coefficient
-log10(Pval)
3
2
1
Fig. 3. Spearman correlation analysis of TMB and DR3 expression. RNA-sequencing expression (level 3) profiles and corresponding clinical information for DR3 were downloaded from the TCGA dataset (https://portal.gdc.com). All the analysis methods and R packages were implemented by R version 4.0.3. If not stated otherwise, two-group data was performed by the Wilcox test. P values less than 0.05 were considered statistically significant (*P < 0.05).
A
Hazard Ratio
| Cancer | Pvalue | Hazard Ratio(95% CI) | B Cancer | Pvalue | Hazard Ratio(95% CI) | ||
|---|---|---|---|---|---|---|---|
| ACC | 2.06e-03 | 1.21(1.07,1.36) | ACC | 1.07e-01 | 1.86(0.875,3.95) | ||
| BLCA | 9.36e-02 | 0.858(0.718,1.03) | BLCA | 3.97e-01 | 0.88(0.655,1.18) | ||
| BRCA | 4.25e-01 | 0.986(0.953,1.02) | BRCA | 4.58e-02 | 0.722(0.525,0.994) | ||
| CESC | 6.44e-01 | 0.94(0.724,1.22) | CESC | 1.8e-01 | 0.727(0.456,1.16) | ||
| CHOL | 4.26e-01 | 0.801(0.464,1.38) | CHOL | 6.54e-01 | 0.801(0.304,2.11) | ||
| COAD | 2.8e-02 | 1.29(1.03,1.61) | COAD | 8.67e-01 | 1.03(0.7,1.53) | ||
| DLBC | 8.5e-01 | 1.01(0.91,1.12) | DLBC | 5.98e-01 | 1.47(0.349,6.24) | ||
| ESCA | 5.23e-01 | 1.1(0.823,1.47) | ESCA | 6.95e-01 | 1.1(0.677,1.79) | ||
| GBM | 1.09e-01 | 1.03(0.992,1.08) | GBM | 3.53e-01 | 1.19(0.828,1.7) | ||
| HNSC | 1.73e-03 | 0.789(0.681,0.915) | HNSC | 4.64e-03 | 0.676(0.516,0.887) | ||
| KICH | 7.26e-01 | 1.26(0.347,4.56) | KICH | 8.43e-01 | 0.876(0.235,3.27) | ||
| KIRC | 2.84e-05 | 1.05(1.03,1.07) | KIRC | 6.37e-02 | 1.33(0.984,1.79) | ||
| KIRP | 7.92e-01 | 0.989(0.915,1.07) | KIRP | 2.58e-01 | 0.7(0.378,1.3) | ||
| LAML | 4.27e-01 | 1.08(0.898,1.29) | LAML | 6.17e-01 | 1.11(0.731,1.7) | ||
| LGG | 3.72e-01 | 1.02(0.975,1.07) | LGG | 2.19e-01 | 1.25(0.875,1.79) | ||
| LIHC | 2.24e-01 | 1.02(0.986,1.06) | LIHC | 8.03e-01 | 0.957(0.678,1.35) | ||
| LUAD | 2.33e-01 | 0.922(0.807,1.05) | LUAD | 5.77e-01 | 0.92(0.687,1.23) | ||
| LUSC | 8.86e-01 | 1.01(0.892,1.14) | LUSC | 7.86e-01 | 0.963(0.733,1.26) | ||
| MESO | 1.75e-02 | 1.06(1.01,1.12) | MESO | 5.87e-02 | 1.57(0.983,2.52) | ||
| OV | 5.69e-01 | 1.04(0.906,1.2) | OV | 3.36e-01 | 1.14(0.876,1.47) | ||
| PAAD | 7.21e-01 | 0.995(0.965,1.02) | PAAD | 6.07e-01 | 0.898(0.595,1.35) | ||
| PCPG | 5.43e-01 | 0.776(0.343,1.76) | PCPG | 3.23e-01 | 0.437(0.085,2.26) | ||
| PRAD | 4.05e-01 | 1.09(0.887,1.34) | PRAD | 1.58e-01 | 2.66(0.683,10.3) | ||
| READ | 8.93e-01 | 0.97(0.619,1.52) | READ | 6.63e-01 | 1.19(0.543,2.62) | ||
| SARC | 4.82e-01 | 1.01(0.982,1.04) | SARC | 3.43e-01 | 1.21(0.815,1.8) | ||
| SKCM | 5.38e-04 | 0.761(0.651,0.888) | SKCM | 2.42e-05 | 0.557(0.425,0.731) | ||
| STAD | 3.06e-01 | 0.913(0.766,1.09) | STAD | 4.24e-01 | 0.875(0.631,1.21) | ||
| TGCT | 6.62e-01 | 0.978(0.886,1.08) | TGCT | 3.65e-01 | 0.352(0.037,3.38) | ||
| THCA | 4.35e-01 | 1.06(0.92,1.21) | THCA | 5.3e-01 | 0.722(0.262,1.99) | ||
| THYM | 7.88e-02 | 1.89(0.93,3.82) | THYM | 4.73e-02 | 8.21(1.02,65.8) | ||
| UCEC | 9.45e-01 | 0.991(0.778,1.26) | UCEC | 2.74e-01 | 0.793(0.523,1.2) | ||
| UCS | 4.89e-01 | 0.988(0.953,1.02) | UCS | 9.93e-01 | 0.997(0.509,1.95) | ||
| UVM | 4.74e-01 | 1.21(0.723,2.01) | UVM | 7.86e-01 | 1.13(0.472,2.7) | ||
| 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Hazard Ratio | 0.037 15 25 35 45 55 65 | ||||||
Fig. 4. Pan-cancer prognostic analysis of DR3. RNA-sequencing expression (level 3) profiles and corresponding clinical information for DR3 were downloaded from the TCGA dataset (https://portal.gdc.com). Using the univariate Cox regression analysis, the forest was used to show the P value, HR, and 95 % CI of each variable through the ‘forestplot ‘R package. All analysis methods and the R package were implemented using R version 4.0.3. If not stated otherwise, two-group data were analyzed by the Wilcoxon test. P values less than 0.05 were considered statistically significant (*P < 0.05). (A) Results of the COX univariate analysis of DR3 in multiple tumors. (B) Univariate KM analysis of DR3 in multiple tumors.
Soluble TL1A
DR3 activator
DR3 inhibitor
DR3
DR3
DR3
TRADD
TRADD
FADD
FADD RIP1
NF-KB
FADD RIP1
NF-KB
RIP1
RIP3
P
P
NF-KB/p65
P
P
NF-KB/p65
IKK’s
IKK’s
Caspase 8
Caspase 8
Caspase 8
MMP9
XIAP
MMP9
XIAP
MLKL
Caspase 3
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Apotosis
Pan-cancer analyses revealed the complex biology of DR3 in tumors: its differential expression pattern in multiple cancer tissues (e.g., significantly up-regulated in 7 cancers such as BLCA, CESC, etc., and down-regulated in 16 cancers such as ACC, BRCA, etc.), and significant associations with immune infiltration, TMB, and patient prognosis (e.g., high DR3 expression in ACC, COAD, etc. suggests a poor prognosis, and protective role in HNSC, SKCM), all suggesting a key role of DR3 in the regulation of the tumor microenvironment. Notably, the bidirectional nature of this role (pro-/anti-cancer) is highly consistent with the DR3 signaling pathway mechanism elaborated in 3: DR3 can activate FADD/ Caspase-8-dependent apoptotic signaling by binding to the ligand TL1A, or trigger RIP1/RIP3/MLKL-mediated necrotic apoptosis; at the same time, there is a remarkable contradiction in its interactions with the NF- KB pathway - some studies support that down-regulation of DR3 inhibits NF-KB pathway-induced apoptosis (e.g., pancreatic cancer, hepatocel- lular carcinoma), whereas others show that up-regulation of DR3 and blocking of NF-KB enhances apoptosis sensitivity (e.g., lung cancer, cervical cancer). Therefore, the tissue-specific differences in DR3 expression and prognosis observed in the pan-cancer analysis may be due to the dual regulatory mechanisms of the DR3 signaling pathway and its complex interactions with microenvironmental factors, high- lighting the need for precise assessment of DR3 in the context of the microenvironment of the specific cancer species before clinical application.
2.6. Regulatory role of DR3 in angiogenesis
DR3 is involved in the regulation of angiogenesis through a variety of mechanisms, with synergistic effects with vascular endothelial growth inhibitors (VEGI, also known as TNFSF15 or TL1A) being particularly notable. VEGI levels have been reported to be negatively correlated with neovascularization in malignant tumors, and the soluble form of VEGI is a potent antiangiogenic factor because of its ability to inhibit endothelial cell proliferation. This inhibition is mediated by death receptor 3 (DR3), which contains a death domain in its cytoplasmic tail capable of inducing apoptosis. A 2015 study revealed that histone deacetylase (HDAC) inhibitors can induce osteosarcoma cell death while inhibiting angiogenesis by activating the VEGI/DR3 pathway. Subsequently, Kumanishi et al. further demonstrated in 2019 that the combined use of HDAC inhibitors and DNA methylation inhibitors synergistically en- hances the anti-tumor effects of this pathway. They also identified a novel mechanism whereby VEGI interferes with VEGF-A, thereby expanding the therapeutic potential of epigenetic therapies for osteo- sarcoma treatment. (Kumanishi et al., 2019; Yamanegi et al., 2015). In addition, therapeutic strategies based on targeted peptides have shown unique advantages. Wang C’s team developed a small peptide, recom- binant vascular basement membrane-derived multifunctional peptide (rVBMDMP), which achieves anti-angiogenic effects by upregulating the phosphorylation of pro-apoptotic signaling proteins, such as death re- ceptor 3 (DR3), and blocking endothelial cell proliferation in melanoma and lung cancer (Wang et al., 2010). Together, these studies suggest that DR3 serves as a core regulatory node and its mediated VEGI signaling
pathway provides an important target for anti-angiogenic therapy. Intervention of this pathway by epigenetic means (e.g., HDAC and DNA methylation inhibitors) or bioactive peptides (e.g., rVBMDMP) effec- tively inhibits tumor angiogenesis and induces tumor cell death, providing a direction for the development of novel antitumor strategies (Fig. 6).
2.7. Immunomodulatory role of DR3
DR3 activates immune cell function through multiple pathways to enhance anti-tumor immune response. Studies have shown that IL-32 significantly enhances the cytotoxicity of natural killer (NK) cells by up-regulating DR3 expression, thereby increasing their potency against colon and prostate cancer cells (Park et al., 2012). In addition, DR3 agonism showed a dual regulatory mechanism in a mouse model of colon cancer: on the one hand, it promoted the clonal expansion of CD8+ T cells by activating the DR3 signaling pathway, and on the other hand, it enhanced their tumor-specific clearance ability (Slebioda et al., 2011). Clinical evidence further showed that the expression of intra-tumoral FasR+DR3+ CD4+ T cells was significantly enhanced in esophageal cancer (EC) tumors, and its distribution was correlated with clinico- pathological features such as lymph node metastasis stage and tumor stage, suggesting that DR3 may become a new target for personalized immunotherapy in EC (Strizova et al., 2020). This feature not only suggests that DR3 can be used as a biomarker to evaluate anti-tumor immune activity, but also correlates significantly with good clinical prognosis of patients (Strizova et al., 2020). Together, these findings reveal the central role of DR3 in coordinating innate and adaptive im- mune responses, and provide a new research direction for tumor immunotherapy (Fig. 7).
2.8. Anti-cancer drugs targeting DR3
Since 2009, several studies have revealed the potential mechanism of various natural compounds in cancer therapy by modulating DR3 and its related signaling pathways. Earlier studies found that Lupeol specifically reduced DR3 mRNA and protein expression in hepatocellular carcinoma cells SMMC7721, thereby inhibiting cell growth and inducing apoptosis (Zhang et al., 2009). In the same year, Fisetin demonstrated inhibitory effects on chemotherapy-resistant cells by inhibiting the DR3-mediated NF-KB pathway in pancreatic cancer AsPC-1 cells (Murtaza et al., 2009). Studies published in 2013 further extended the application of the DR3 pathway, with cordycepin inducing apoptosis in colon cancer HT-29
DR3 activator
DR3
Cancer Cell
IFNYR
IFNY
DAMPs
NK Cell
CD8+T Cell
CD8+T Cell
cells via this pathway, and Lactobacillus casei extracts decreasing the viability of hepatocellular carcinoma Huh7 cells by 77 %, with the mechanism involving elevated DR3 expression accompanied by cell cycle G2/M phase block (Han et al., 2013; Lee et al., 2013). Two inde- pendent studies in 2014 focused on non-small cell lung cancer, in which tectochrysin activated DR3/Fas expression through inhibition of STAT3 phosphorylation, whereas bee venom showed pro-apoptotic effects in both A549 and NCI-H460 cell lines by enhancing DR3 expression and inhibiting NF-KB (Choi et al., 2014; Oh et al., 2014). Follow-up in vivo experiments confirmed that bee venom inhibited cervical tumor growth in mice by regulating FAS/DR3/DR6 expression (Lee et al., 2016). Studies in 2015-2016 further validated the generalization of this mechanism: Polyphyllin VI and VII exhibited dual in vitro/in vivo activity in a lung cancer model by upregulating the DR3-mediated apoptotic pathway, whereas in a mouse model of cervical cancer, snake venom toxin (0.5 and 1 mg/kg) inhibited NF-KB and augmented DR3/DR5 expression by suppressing the tumors (Lee et al., 2016; Lin et al., 2015). In addition to natural compounds, (E)-4-(3-(3,5-dimethoxyphenyl)
VEGI/TL1A
DR3
Caspase 8
VEGI/ VEGF-A
Caspase 3
Apoptosis
Angiogenesis
allyl)-2-methoxyphenol has been found to induce apoptosis in HCT116 and SW480 colon cancer cells through activation of Fas and death re- ceptor 3 in a dose-dependent manner (0-15 µg/ml), and inhibition of the STAT3 and NF-KB pathways suppresses in vivo and in vitro Colon cancer cell growth (Zheng et al., 2015). Nishito Y et al. identified and characterized the testis-specific expression of the E3 ubiquitin ligase MEX, which specifically enhances death receptor (Fas/DR3/DR4)-me- diated apoptosis through SWIM structural domain-dependent self — ubiquitination function (Nishito et al., 2006). These findings systematically reveal the central regulatory role of the DR3 pathway in multiple tumor types, and provide an important theoretical basis for the development of anticancer drugs targeting death receptors (Fig. 8).
Although the aforementioned studies based on cancer cell lines provide crucial mechanistic insights and encouraging preliminary evi- dence for natural compounds targeting the DR3 pathway, it must be noted that these findings possess inherent limitations. In vitro models cannot replicate the complex tumor microenvironment or the pharma- cokinetic processes of compounds in vivo. Consequently, their conclu- sions require validation in animal models that more closely mimic human conditions to assess their genuine therapeutic potential and safety. Nevertheless, these cellular-level studies undoubtedly establish a robust theoretical foundation, confirming DR3 as a valuable anti-cancer target and charting a course for subsequent translational research.
3. Discussion
DR3-mediated signaling plays a complex and seemingly contradic- tory role in tumors, with its ultimate functional output-inducing cell death or promoting cell survival-highly dependent on the specific cellular context. This study and existing evidence indicate that DR3 expression and function exhibit tumor type specificity. For example, in pancreatic and hepatocellular carcinomas, downregulation of DR3 expression and inhibition of NF-KB signaling can effectively induce apoptosis. In contrast, in lung and cervical carcinomas, upregulation of DR3 (usually accompanied by DR5/DR6) and blockade of NF-KB can also strongly promote apoptosis, potentially even reversing TRAIL resistance. This phenomenon, wherein “apoptotic effects can be achieved by inhibiting the NF-KB pathway regardless of the direction of DR3 level changes,” indicates the extraordinary complexity of the DR3 signaling network. It profoundly suggests that single-target regulatory strategies for DR3 may harbor potential risks, while precision-based tumor mo- lecular subtyping will be an essential prerequisite for future exploration of its therapeutic value. It should be noted that these findings currently derive primarily from in vitro cell line experiments, and their general- izability requires validation in more complex in vivo models and across a broader spectrum of tumor types.
In addition to directly inducing cancer cell death, DR3 indirectly inhibits tumor progression through two main pathways. One, by
activating the caspase-3 pathway and regulating the VEGI/VEGF-A balance, it inhibits tumor angiogenesis and disrupts tumor nutrient supply. Two, the DR3-mediated process of tumor cell apoptosis itself, which releases tumor antigens and damage-associated molecular pat- terns (DAMPs), indirectly activates and enhances the anti-tumor response of natural (e.g., NK cells) and adaptive (e.g., CD8+ T cells) immunity. This corroborates the significant positive correlation between DR3 expression and immune cell infiltration (especially CD8+ T cells and NK cells) observed in pan-cancer analyses, highlighting the important role of DR3 as a bridge connecting the intrinsic death program of tumor cells with the body’s anti-tumor immune response.
It is noteworthy that DR3 plays a dual role in immune regulation, a characteristic that renders it particularly distinctive in cancer therapy research. On the one hand, DR3 signaling can co-stimulate effector lymphocytes (such as CD4+ T cells), prompting them to produce pro- inflammatory cytokines and thereby enhance the aggressiveness of im- mune responses; On the other hand, DR3 is constitutively overexpressed on regulatory T cells (Tregs), where it signaling activates and expands Tregs with immunosuppressive functions, thereby maintaining immune homeostasis and suppressing excessive immune responses. This bidi- rectional regulatory capacity positions DR3 as a pivotal node within the immune regulatory network, explaining its potentially divergent and seemingly contradictory roles across different cancer types and immune microenvironments (Liman et al., 2024; Rodriguez-Barbosa et al., 2020).
Although preclinical studies (such as those involving TL1A agonists) have demonstrated the antitumor potential of targeting the DR3 pathway, no anticancer drugs directly targeting DR3 are currently available on the market. The expression levels of DR3 and its prognostic significance exhibit marked tumor type specificity. For instance, in adrenocortical carcinoma (ACC), high DR3 expression constitutes a risk factor, whereas in cutaneous melanoma (SKCM), elevated expression correlates with a protective prognosis. This heterogeneity poses chal- lenges for drug development whilst simultaneously indicating its po- tential clinical value.
Moreover, the precise regulation of the DR3 signaling pathway is further influenced by its structural diversity. Multiple mRNA splicing variants of DR3 exist, exhibiting significant differences in both structure and function (Borysenko et al., 2006; Grenet et al., 1998; Utkin et al., 2013; Warzocha et al., 1998). These isoforms, generated through alternative splicing, may perform distinct roles in signal transduction and potentially exert negative regulatory functions. Among these, the membrane-integrated full-length receptor and the truncated soluble isoform play antagonistic roles in immune regulation: the former, as a typical type I transmembrane protein, mediates signal transduction via its intracellular death domain. Upon binding to its ligand TL1A, it ac- tivates downstream pathways such as NF-KB and MAPK, thereby driving T-cell activation, proliferation, and the release of inflammatory cyto- kines. The latter, lacking transmembrane and intracellular domains,
· Lupeol · Fisetin
· Cordycepin · Lactobacillus casei extracts
· Tectochrysin · Bee venom
· PolyphylinVI/VII
· Sanke venom toxin
Natural compound
2006
2009
2013
2014
2015
Synthetic substances
· E3 ubiqutin ligase MEX
· (E)-4-(3-(3,5- dimethoxyphenyl)all yl)-2-methoxyphenol
exists extracellularly in a secreted form. Although it binds TL1A with high affinity, it cannot initiate intracellular signaling. Consequently, it functions as an endogenous decoy receptor, negatively regulating the activation intensity of the DR3 pathway by competitively inhibiting ligand-receptor interactions. Together, these two receptor types consti- tute a finely balanced system of crucial importance for maintaining immune homeostasis.
Beyond this regulatory network, an important exogenous decoy re- ceptor exists-DcR3 (Decoy Receptor 3). DcR3 binds with high affinity to multiple death ligands, including TL1A (such as FasL and LIGHT), thereby inhibiting apoptosis and inflammatory signaling mediated by these ligands (Ge et al., 2011; Hsieh and Lin, 2017). DcR3 is widely overexpressed in multiple solid tumors (such as glioma, gastric cancer, colorectal cancer, ovarian cancer, and breast cancer)(Arakawa et al., 2005; Liang et al., 2009; Macher-Goeppinger et al., 2008; Zhang et al., 2017). It can bind death ligands, including TL1A, with high affinity, thereby inhibiting the apoptosis and inflammatory signals they mediate. TL1A exhibits high expression in multiple tumor tissues. As early as 2018, studies utilizing three mouse models-AOM/DSS-induced, xeno- graft, and experimental metastasis-consistently confirmed that TL1A is a key factor driving the initiation, growth, and distant metastasis of colorectal cancer (Niu et al., 2018). In recent years, its tumor-promoting mechanism has been further elucidated: Niu et al. discovered that knocking down TL1A inhibits the proliferation, metastasis, and epithelial-mesenchymal transition of colorectal cancer cells by sup- pressing the TGF-61/Smad3 pathway (Niu et al., 2024). Furthermore, studies in other solid tumors have elucidated the mechanism of action of TL1A. For instance, Jiang et al. reported that the RNA-binding protein ELAVL1 enhances the stability of TL1A mRNA by binding to its 3’UTR region, thereby activating the PI3K/Akt signaling pathway and pro- moting malignant progression in gastric cancer (Jiang et al., 2025; Niu et al., 2024). At the mechanistic level, elevated DcR3 expression competitively binds TL1A, blocking its interaction with membrane-bound DR3 (Siakavellas and Bamias, 2015). This impairs the pathway’s pro-inflammatory and pro-apoptotic effects, aiding tumor cells in immune evasion and angiogenesis, ultimately exacerbating tumor progression and poor prognosis. Notably, DcR3 expression levels carry significant pathological implications: its “activated” state corre- lates with inflammatory repair, whereas “inactivation” promotes tumor apoptosis (Hsieh and Lin, 2017). Collectively, DcR3’s specific over- expression in tumor tissues and its pivotal regulatory role in TL1A signaling render it a highly promising biomarker and therapeutic target.
The abnormal expression of DR3 and its isoforms is closely associated with tumor initiation and progression. Research groups, including Gout et al., have demonstrated that high-molecular-weight DR3 variants are significantly overexpressed in colorectal cancer cell lines such as HT29 and Lovo, as well as in primary colorectal cancer tissues, whereas this phenomenon is absent in normal colonic tissue. Functional experiments confirm that knocking out DR3 significantly inhibits the metastatic ca- pacity of cancer cells (Gout et al., 2006). Moreover, similar DR3 variant molecules lacking the transmembrane region and death domain are also present in osteosarcoma and neuroblastoma, where these mutations enhance tumor cells’ resistance to apoptosis and chemotherapeutic agents (Grenet et al., 1998; Warzocha et al., 1998). It is noteworthy that in colorectal cancer cells, E-selectin enhances tumor cell survival by activating the PI3K/NFKB signaling pathway mediated by DR3. Partic- ularly in metastatic colorectal cancer cell lines such as HT29 and SW620, the high expression of a DR3 splice variant lacking transmembrane and death domains further reveals the potential role of this molecule in tumor progression (Porquet et al., 2011).
Based on the aforementioned research, DR3 and its isoforms exhibit multiple potential applications in clinical settings. Tissue DR3 expres- sion levels may be utilized to identify patient subgroups with differing prognostic risks, thereby guiding adjuvant treatment decisions. DcR3 levels may serve as readily monitorable liquid biomarkers. Studies indicate that DcR3 is highly expressed in multiple tumors, with its levels
correlating with disease progression and prognosis. Regular monitoring of DcR3 levels in blood may enable dynamic assessment of disease progression and treatment response. Furthermore, the expression profile of DR3 isoforms may provide more refined stratification information. Different DR3 isoforms may possess distinct signaling functions, potentially even exerting dominant negative effects. By analyzing the expression patterns of specific isoforms, more precise predictions of treatment response and patient prognosis may be achievable. Crucially, the application of DR3 biomarkers may necessitate combined analysis with other immunological markers (such as PD-L1, tumor-infiltrating lymphocyte levels, etc.) to establish a comprehensive immune scoring system. This multi-parameter assessment approach holds promise for more accurate prediction of treatment response, guiding the selection of diverse therapeutic strategies including immunotherapy, chemotherapy, and targeted therapies. Future research may further incorporate ma- chine learning and artificial intelligence methodologies to conduct in- depth analysis of multidimensional integrated datasets, thereby vali- dating and expanding upon the DR3-related regulatory patterns and clinical value revealed in this paper.
It should be noted that this study is primarily based on cell line ex- periments. While these findings provide insights into the function of DR3, their conclusions are limited by the absence of a genuine tumor microenvironment. Future research must validate these findings in pri- mary patient samples. Given the complexity of DR3 signaling, thera- peutic strategies must be precisely tailored to the molecular characteristics of individual tumors to prevent ineffective or adverse reactions arising from generalized application.
Authors contribution
Conceptualization, X.W .; methodology, X.W .; software, X.W .; formal analysis, X.W .; investigation, W.F., J.D., Z. X., Q. L .; resources, Y.L .; data curation, W.F., J.D., Z. X., Q. L .; writing-original draft preparation, W. F. and J.D .; writing-review and editing, X.W .; visualization, W.F. and X.W .; funding acquisition, X.W. and W. F.
Institutional Review Board Statement
Not applicable.
Ethical approval
Not applicable.
Funding
This research was funded by the Natural Science Foundation of Guangxi Zhuang Autonomous Region (2025GXNSFAA069334); the Innovation Project of Guangxi Graduate Education of GXUCM (YCSY2025099); the visiting Scholar Program of Bagui (Xueni Wang).
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgments
None.
Data availability
Not applicable.
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Wenxuan Fang, a master’s candidate in Traditional Chinese Medicine, specializes in the antitumor pharmacology research of natural products. She has published multiple aca- demic papers in international journals and participated in several projects related to natural product antitumor research.
Junfang Du, M.D., Ph.D., a physician with extensive experience in both clinical practice and laboratory research. Her primary research focus centers on the anti-tumor research of Traditional Chinese Medicine and ethnic medicine.
Zedong Xu, Xu Zedong, a master’s candidate in pharmacology, is currently participating in multiple research projects on tumor pharmacology and the antitumor mechanisms of natural products.
Qiuyu Liu, a master’s candidate in Traditional Chinese Medicine, specializes in the anti- tumor pharmacology research of natural products. She is currently participating in mul- tiple research projects on tumor pharmacology and the antitumor mechanisms of natural products.
Yonghong Liu, Ph.D., a senior researcher, possesses extensive experience in the execution and management of scientific research projects. He has published over 300 papers in renowned journals and holds multiple drug-related invention patents. His primary research focus is the development of innovative drugs.
Xueni Wang, M.D., Ph.D., an associate researcher, possesses extensive experience in anticancer drug research and has published over 30 papers in renowned academic jour- nals. She has long been dedicated to studying the pharmacological effects of anticancer drugs and their molecular mechanisms, having obtained multiple invention patents.