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Volume 32,Issue 12,2025 Table of Contents
2025, 32(12):1211-1220.
Abstract:
[Abstract] Lymphocyte activation gene-3 (LAG-3, CD223) plays a pivotal role in regulating T-cell function and maintaining immune homeostasis and is widely recognized as the most promising co-inhibitory immune checkpoint following programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). LAG-3 is highly expressed on activated T cells and exhausted T cells (TEX) within the tumor microenvironment, where its inhibitory activity constitutes a critical mechanism underlying tumor immune evasion. In contrast to PD-1 and CTLA-4, LAG-3 exhibits distinct regulatory features in modulating T-cell receptor (TCR) signaling strength and restricting T-cell proliferation and effector cytokine production. Consequently, LAG-3 is broadly regarded as one of the most clinically promising immune checkpoint targets beyond PD-1 and CTLA-4. In recent years, advances in the understanding of LAG-3 molecular structure, extracellular ligand interactions (e. g., major histocompatibility complex class Ⅱ [MHC Ⅱ]and fibrinogen-like protein 1 [FGL1]), and intracellular signaling mechanisms have substantially accelerated the development of LAG-3-targeted therapies. Multiple monoclonal antibodies against LAG-3 have entered clinical trials and have demonstrated encouraging therapeutic potential, particularly in combination with PD-1 inhibitors. This review systematically summarizes and discusses the molecular structure of LAG-3, its ligand interactions and downstream signaling pathways, as well as recent advances and future prospects in LAG-3-targeted drugs and clinical therapeutic strategies, with the aim of providing a comprehensive reference for further mechanistic studies and the optimization of future LAG-3-based immunotherapies.
[Abstract] Lymphocyte activation gene-3 (LAG-3, CD223) plays a pivotal role in regulating T-cell function and maintaining immune homeostasis and is widely recognized as the most promising co-inhibitory immune checkpoint following programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). LAG-3 is highly expressed on activated T cells and exhausted T cells (TEX) within the tumor microenvironment, where its inhibitory activity constitutes a critical mechanism underlying tumor immune evasion. In contrast to PD-1 and CTLA-4, LAG-3 exhibits distinct regulatory features in modulating T-cell receptor (TCR) signaling strength and restricting T-cell proliferation and effector cytokine production. Consequently, LAG-3 is broadly regarded as one of the most clinically promising immune checkpoint targets beyond PD-1 and CTLA-4. In recent years, advances in the understanding of LAG-3 molecular structure, extracellular ligand interactions (e. g., major histocompatibility complex class Ⅱ [MHC Ⅱ]and fibrinogen-like protein 1 [FGL1]), and intracellular signaling mechanisms have substantially accelerated the development of LAG-3-targeted therapies. Multiple monoclonal antibodies against LAG-3 have entered clinical trials and have demonstrated encouraging therapeutic potential, particularly in combination with PD-1 inhibitors. This review systematically summarizes and discusses the molecular structure of LAG-3, its ligand interactions and downstream signaling pathways, as well as recent advances and future prospects in LAG-3-targeted drugs and clinical therapeutic strategies, with the aim of providing a comprehensive reference for further mechanistic studies and the optimization of future LAG-3-based immunotherapies.
2025, 32(12):1221-1227.
Abstract:
[Abstract] Objective: To establish a mice ascitic tumor model using ID8 cells and evaluate the immune cell composition and cytokine network features under different tumor burdens, providing experimental evidence for the study of the ovarian cancer immune microenvironment. Methods: Female C57BL/6 mice aged 6-8 weeks were selected and divided into two groups: a control group (without ID8 cell injection) and an ID8 cell group. The ID8 cell group was further subdivided into three subgroups based on the number of injected cells: 1 × 10? group, 5 × 10? group, and 1 × 10? group. Multiplex cytokine detection technology was used to measure the concentrations of IFN-γ, IL-2, IL-6, TNF-α, CCL2, CXCL10, IL-17, and IL-1β in the serum and ascites. Flow cytometry was employed to determine the proportions of CD3? T cells, CD4? T cells, CD8? T cells, CD19? B cells, F4/80?CD11b? macrophages, myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg cells), and natural killer (NK) cells in the ascites. Results: After intraperitoneal transplantation of ID8 cells, the body weight and abdominal circumference of mice in the ID8 cell group were significantly increased (all P < 0.05). In the ID8 cell group, the serum levels of IL-6, IL-2, TNF-α, and IL-1β were significantly elevated (all P < 0.05), while the serum level of CCL2 was significantly decreased (P < 0.05); no significant changes were observed in the serum levels of IFN-γ, IL-17, and CXCL10. Compared with the serum cytokine levels in the ID8 cell group, the ascites levels of IL-6, IL-2, TNF-α, CCL2, CXCL10, and IL-17 were significantly higher (all P < 0.05), whereas the ascites levels of IL-1β and IFN-γ showed no significant changes. Analysis of immune cell proportions in the ascites of the ID8 cell group revealed that CD19? B cells accounted for the highest proportion, followed by F4/80? CD11b? macrophages and CD3? T cells, while NK cells accounted for the lowest proportion. Conclusion：：The ID8 cell ascitic tumor model can effectively simulate the imbalance between local immune activation and systemic inflammatory response in ovarian cancer. Tumor burden modulates immune landscape by regulating immune cells such as T cells and macrophages, as well as the differential cytokine networks between serum and ascites, providing new targets for ovarian cancer immunotherapy.
[Abstract] Objective: To establish a mice ascitic tumor model using ID8 cells and evaluate the immune cell composition and cytokine network features under different tumor burdens, providing experimental evidence for the study of the ovarian cancer immune microenvironment. Methods: Female C57BL/6 mice aged 6-8 weeks were selected and divided into two groups: a control group (without ID8 cell injection) and an ID8 cell group. The ID8 cell group was further subdivided into three subgroups based on the number of injected cells: 1 × 10? group, 5 × 10? group, and 1 × 10? group. Multiplex cytokine detection technology was used to measure the concentrations of IFN-γ, IL-2, IL-6, TNF-α, CCL2, CXCL10, IL-17, and IL-1β in the serum and ascites. Flow cytometry was employed to determine the proportions of CD3? T cells, CD4? T cells, CD8? T cells, CD19? B cells, F4/80?CD11b? macrophages, myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg cells), and natural killer (NK) cells in the ascites. Results: After intraperitoneal transplantation of ID8 cells, the body weight and abdominal circumference of mice in the ID8 cell group were significantly increased (all P < 0.05). In the ID8 cell group, the serum levels of IL-6, IL-2, TNF-α, and IL-1β were significantly elevated (all P < 0.05), while the serum level of CCL2 was significantly decreased (P < 0.05); no significant changes were observed in the serum levels of IFN-γ, IL-17, and CXCL10. Compared with the serum cytokine levels in the ID8 cell group, the ascites levels of IL-6, IL-2, TNF-α, CCL2, CXCL10, and IL-17 were significantly higher (all P < 0.05), whereas the ascites levels of IL-1β and IFN-γ showed no significant changes. Analysis of immune cell proportions in the ascites of the ID8 cell group revealed that CD19? B cells accounted for the highest proportion, followed by F4/80? CD11b? macrophages and CD3? T cells, while NK cells accounted for the lowest proportion. Conclusion：：The ID8 cell ascitic tumor model can effectively simulate the imbalance between local immune activation and systemic inflammatory response in ovarian cancer. Tumor burden modulates immune landscape by regulating immune cells such as T cells and macrophages, as well as the differential cytokine networks between serum and ascites, providing new targets for ovarian cancer immunotherapy.
2025, 32(12):1228-1235.
Abstract:
[Abstract] Objective: To investigate the effect of 2'-fucosyllactose (2'-FL) on immune checkpoint inhibitor-induced colitis (ICIC) in mice and its possible mechanisms. Methods: BALB/c mice were randomly assigned into the normal control (NC) group, dextran sulfate sodium (DSS) group, ICIC group, and ICIC + 2'-FL group, using a random number table method. Mice in the DSS group were provided with 3.5% DSS-containing drinking water for seven days to induce colonic inflammation. The ICIC group was intraperitoneally injected of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4; dose: 150 μg) on day 0 and day 4, while simultaneously consuming 3.5% DSS-containing drinking water. The ICIC + 2'-FL group received daily intragastric administration of 2'-FL (150 mg/[kg·d]) concurrently with the establishment of ICIC model. Changes in body weight and disease activity index (DAI) were statistically analyzed. On day 7, all mice were sacrificed, and the colon length was measured. Hematoxylin and eosin (H&E) staining was performed to observe histomorphological changes in colon tissues across groups. Immunohistochemistry (IHC) was conducted to assess the infiltration of CD3+ T cells and CD19+ B cells in colonic tissues. RNA sequencing (RNA-seq) was performed on colon tissues. The differentially expressed genes (DEGs) were subjected to Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Results: Compared with the NC and DSS groups, the ICIC group showed significant body weight loss, elevated DAI scores, and shorter colon length (all P <0.05); besides, the colon mucosal integrity was damaged, with typical ulcerative lesions. Compared with the ICIC group, ICIC + 2'-FL group demonstrated significantly alleviated body weight loss, reduced DAI score, and restored colon length (all P < 0.05). Transcriptomic results revealed 51 DEGs in the ICIC + 2'-FL group (vs ICIC group). GO functional annotation and KEGG enrichment analysis suggested that the protective effect of 2'-FL against ICIC-like symptoms might be associated with upregulation of signaling pathways related to B cell receptor, B cell proliferation regulation, inflammatory responses, and tissue repair. Conclusion: Human milk oligosaccharide 2'-FL significantly alleviates the pathological progression of ICIC by modulating B-cell receptor-related signaling pathways and pathways associated with inflammation responses and tissue repair, thereby reducing colonic damage in ICIC mice.
[Abstract] Objective: To investigate the effect of 2'-fucosyllactose (2'-FL) on immune checkpoint inhibitor-induced colitis (ICIC) in mice and its possible mechanisms. Methods: BALB/c mice were randomly assigned into the normal control (NC) group, dextran sulfate sodium (DSS) group, ICIC group, and ICIC + 2'-FL group, using a random number table method. Mice in the DSS group were provided with 3.5% DSS-containing drinking water for seven days to induce colonic inflammation. The ICIC group was intraperitoneally injected of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4; dose: 150 μg) on day 0 and day 4, while simultaneously consuming 3.5% DSS-containing drinking water. The ICIC + 2'-FL group received daily intragastric administration of 2'-FL (150 mg/[kg·d]) concurrently with the establishment of ICIC model. Changes in body weight and disease activity index (DAI) were statistically analyzed. On day 7, all mice were sacrificed, and the colon length was measured. Hematoxylin and eosin (H&E) staining was performed to observe histomorphological changes in colon tissues across groups. Immunohistochemistry (IHC) was conducted to assess the infiltration of CD3+ T cells and CD19+ B cells in colonic tissues. RNA sequencing (RNA-seq) was performed on colon tissues. The differentially expressed genes (DEGs) were subjected to Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Results: Compared with the NC and DSS groups, the ICIC group showed significant body weight loss, elevated DAI scores, and shorter colon length (all P <0.05); besides, the colon mucosal integrity was damaged, with typical ulcerative lesions. Compared with the ICIC group, ICIC + 2'-FL group demonstrated significantly alleviated body weight loss, reduced DAI score, and restored colon length (all P < 0.05). Transcriptomic results revealed 51 DEGs in the ICIC + 2'-FL group (vs ICIC group). GO functional annotation and KEGG enrichment analysis suggested that the protective effect of 2'-FL against ICIC-like symptoms might be associated with upregulation of signaling pathways related to B cell receptor, B cell proliferation regulation, inflammatory responses, and tissue repair. Conclusion: Human milk oligosaccharide 2'-FL significantly alleviates the pathological progression of ICIC by modulating B-cell receptor-related signaling pathways and pathways associated with inflammation responses and tissue repair, thereby reducing colonic damage in ICIC mice.
LIN Yan
,
YU Shuangjian
,
JIA Sifan
,
LI Feiyu
,
ZHAO Chenpu
,
DONG Zhiming
,
SHEN Supeng
,
LIANG Jia
,
GUO Yanli
2025, 32(12):1236-1246.
Abstract:
[Abstract] Objective: To investigate the expression of coatomer protein complex subunit beta 1 (COPB1) in esophageal squamous cell carcinoma (ESCC) and its impact on the malignant biological behavior of ESCC cells, as well as the underlying mechanism of action and its clinical significance. Methods: A total of 82 pairs of ESCC tissues and adjacent non-cancerous were collected from the biobank of the Fourth Hospital of Hebei Medical University during 2014 and 2018. Normal esophageal squamous cells (HEEC) and ESCC cell lines (KYSE-150, KYSE-170, Eca109, TE1, KYSE-30, KYSE-450) were routinely cultured. The pcDNA3.1-vector (empty vector), pcDNA3.1-COPB1 vector, si-NC, and si-COPB1 were transfected into KYSE-150 and TE1 cells using transfection reagents. The resulting groups were designated as the NC, COPB1-OE, si-NC, and si-COPB1 groups, respectively. A comprehensive database analysis was conducted to assess the mRNA expression of COPB1 in pan-cancer tissues and its correlation with immune cell infiltration. Quantitative real-time polymerase chain reaction (qPCR) was utilized to assess the mRNA expression of COPB1, PIK3CB, CD68, CD163, CD206, ARG1, and IL-10 in ESCC tissues and cells. Western blotting (WB) analysis was performed to detect COPB1, PI3K, CD68, CD163, CD206 and p-AKT protein expression in ESCC tissues and various cell groups. Colony formation and MTS assays were conducted to assess cell proliferation, while wound healing assay and Transwell assay were used to determine cell migration and invasion. Immunohistochemistry (IHC) was employed to detect the protein expression of COPB1 and CD206 in ESCC tissues. A macrophage model was established using human monocytic leukemia cells (THP-1). Macrophage polarization was induced with phorbol myristate acetate (PMA), interleukin-3 (IL-3), IL-4, and ESCC cell supernatant. WB and qPCR were performed to detect the protein and mRNA expression of CD68 and CD206, respectively. Results: COPB1 was highly expressed in both pan-cancer and ESCC tissues, and its expression was associated with lymph node metastasis and TNM staging (both P < 0.01). ESCC patients with high COPB1 expression exhibited shorter overall survival (P < 0.05), making COPB1 a potential diagnostic biomarker for ESCC. COPB1 was also highly expressed in KYSE-150 and TE1 cells (both P < 0.05). Overexpression or knockdown of COPB1 significantly inhibited or promoted the proliferation, migration and invasion capabilities of KYSE-150 and TE1 cells (both P < 0.05). Differentially expressed genes induced by COPB1 expression changes were primarily enriched in the PI3K/AKT pathway (both P < 0.001), and COPB1 activated the PI3K/AKT pathway (P < 0.05). Additionally, high COPB1 expression increased M2 macrophage infiltration (P < 0.05) and promoted TAM/M2 polarization (P < 0.05). Conclusion: COPB1 is highly expressed in ESCC tissues and can activate the PI3K/AKT pathway and modulates the tumor immune microenvironment, thereby promoting ESCC occurrence and development. COPB1 holds promise as a diagnostic and prognostic biomarker, as well as a therapeutic target for ESCC.
[Abstract] Objective: To investigate the expression of coatomer protein complex subunit beta 1 (COPB1) in esophageal squamous cell carcinoma (ESCC) and its impact on the malignant biological behavior of ESCC cells, as well as the underlying mechanism of action and its clinical significance. Methods: A total of 82 pairs of ESCC tissues and adjacent non-cancerous were collected from the biobank of the Fourth Hospital of Hebei Medical University during 2014 and 2018. Normal esophageal squamous cells (HEEC) and ESCC cell lines (KYSE-150, KYSE-170, Eca109, TE1, KYSE-30, KYSE-450) were routinely cultured. The pcDNA3.1-vector (empty vector), pcDNA3.1-COPB1 vector, si-NC, and si-COPB1 were transfected into KYSE-150 and TE1 cells using transfection reagents. The resulting groups were designated as the NC, COPB1-OE, si-NC, and si-COPB1 groups, respectively. A comprehensive database analysis was conducted to assess the mRNA expression of COPB1 in pan-cancer tissues and its correlation with immune cell infiltration. Quantitative real-time polymerase chain reaction (qPCR) was utilized to assess the mRNA expression of COPB1, PIK3CB, CD68, CD163, CD206, ARG1, and IL-10 in ESCC tissues and cells. Western blotting (WB) analysis was performed to detect COPB1, PI3K, CD68, CD163, CD206 and p-AKT protein expression in ESCC tissues and various cell groups. Colony formation and MTS assays were conducted to assess cell proliferation, while wound healing assay and Transwell assay were used to determine cell migration and invasion. Immunohistochemistry (IHC) was employed to detect the protein expression of COPB1 and CD206 in ESCC tissues. A macrophage model was established using human monocytic leukemia cells (THP-1). Macrophage polarization was induced with phorbol myristate acetate (PMA), interleukin-3 (IL-3), IL-4, and ESCC cell supernatant. WB and qPCR were performed to detect the protein and mRNA expression of CD68 and CD206, respectively. Results: COPB1 was highly expressed in both pan-cancer and ESCC tissues, and its expression was associated with lymph node metastasis and TNM staging (both P < 0.01). ESCC patients with high COPB1 expression exhibited shorter overall survival (P < 0.05), making COPB1 a potential diagnostic biomarker for ESCC. COPB1 was also highly expressed in KYSE-150 and TE1 cells (both P < 0.05). Overexpression or knockdown of COPB1 significantly inhibited or promoted the proliferation, migration and invasion capabilities of KYSE-150 and TE1 cells (both P < 0.05). Differentially expressed genes induced by COPB1 expression changes were primarily enriched in the PI3K/AKT pathway (both P < 0.001), and COPB1 activated the PI3K/AKT pathway (P < 0.05). Additionally, high COPB1 expression increased M2 macrophage infiltration (P < 0.05) and promoted TAM/M2 polarization (P < 0.05). Conclusion: COPB1 is highly expressed in ESCC tissues and can activate the PI3K/AKT pathway and modulates the tumor immune microenvironment, thereby promoting ESCC occurrence and development. COPB1 holds promise as a diagnostic and prognostic biomarker, as well as a therapeutic target for ESCC.
2025, 32(12):1247-1252.
Abstract:
[Abstract] Objective: To investigate the effect of ginsenoside Rg3 (GRG3) on the immune escape of breast cancer cells by regulating pentose phosphate pathway (PPP) mediated by PI3K/AKT/mTOR signaling pathway. Methods: MCF7 cells were routinely cultured and divided into five groups: control group, GRG3 low-dose (GRG3-L) group, GRG3 high-dose (GRG3-H) group, GRG3-H + 740Y-P (PI3K activator) group, and Ly294002 (PI3K inhibitor) group. Colony formation assay, flow cytometry, DCFH-DA fluorescent probe assay, and WB were used to evaluate cell proliferation, apoptosis, ROS levels, and the expression of proteins related to the PPP and the PI3K/Akt/mTOR signaling pathway in each group, respectively. The cytotoxic effect of NK-92MI cells against MCF7 cells was measured using the CCK-8 assay. ELISA was employed to detect the levels of CXCL-2, CXCL-8, G6PD, and NADPH in MCF7 cells, as well as the levels of TNF-α and IFN-γ in the culture supernatant of co-cultured cells. Results: GRG3 significantly suppressed the clonogenic ability of MCF7 cells (all P < 0.05), promoted apoptosis of MCF7 cells (all P < 0.05), and reduced the levels of CXCL-2, CXCL-8, G6PD, NADPH, and ROS in MCF7 cells (all P < 0.05). Additionally, GRG3 inhibited the PPP and PI3K/Akt/mTOR signaling pathways (all P < 0.05), promoted the secretion of TNF-α and IFN- γ by NK-92MI cells (all P < 0.05), and enhanced the cytotoxicity of NK-92MI cells against MCF7 cells (all P < 0.05). These effects were partially reversed by 740Y-P (P < 0.05). Conclusion: GRG3 inhibits the biological behavior and immune escape of breast cancer MCF7 cells by suppressing the PI3K/AKT/ mTOR pathway-mediated PPP.
[Abstract] Objective: To investigate the effect of ginsenoside Rg3 (GRG3) on the immune escape of breast cancer cells by regulating pentose phosphate pathway (PPP) mediated by PI3K/AKT/mTOR signaling pathway. Methods: MCF7 cells were routinely cultured and divided into five groups: control group, GRG3 low-dose (GRG3-L) group, GRG3 high-dose (GRG3-H) group, GRG3-H + 740Y-P (PI3K activator) group, and Ly294002 (PI3K inhibitor) group. Colony formation assay, flow cytometry, DCFH-DA fluorescent probe assay, and WB were used to evaluate cell proliferation, apoptosis, ROS levels, and the expression of proteins related to the PPP and the PI3K/Akt/mTOR signaling pathway in each group, respectively. The cytotoxic effect of NK-92MI cells against MCF7 cells was measured using the CCK-8 assay. ELISA was employed to detect the levels of CXCL-2, CXCL-8, G6PD, and NADPH in MCF7 cells, as well as the levels of TNF-α and IFN-γ in the culture supernatant of co-cultured cells. Results: GRG3 significantly suppressed the clonogenic ability of MCF7 cells (all P < 0.05), promoted apoptosis of MCF7 cells (all P < 0.05), and reduced the levels of CXCL-2, CXCL-8, G6PD, NADPH, and ROS in MCF7 cells (all P < 0.05). Additionally, GRG3 inhibited the PPP and PI3K/Akt/mTOR signaling pathways (all P < 0.05), promoted the secretion of TNF-α and IFN- γ by NK-92MI cells (all P < 0.05), and enhanced the cytotoxicity of NK-92MI cells against MCF7 cells (all P < 0.05). These effects were partially reversed by 740Y-P (P < 0.05). Conclusion: GRG3 inhibits the biological behavior and immune escape of breast cancer MCF7 cells by suppressing the PI3K/AKT/ mTOR pathway-mediated PPP.
2025, 32(12):1253-1261.
Abstract:
[Abstract] Objective: To investigate the expression of ubiquitin-specific protease 20 (USP20) in pancreatic cancer tissues and its role and molecular mechanism in the proliferation and migration of pancreatic cancer cells. Methods: The Cancer Genome Atlas (TCGA) database was used to analyze USP20 and TWIST family bHLH transcription factor (TWIST) expression in pancreatic cancer tissues. Kaplan-Meier curve analysis was used evaluate their correlation with patient prognosis. Normal pancreatic cells (HPNE) and pancreatic cancer cells (MIAPaca2, BxPC3, PANC1, SW1990, Aspc1) were routinely cultured, and USP20 protein expression was detected by Western blot (WB). PANC1 and SW1990 cells were divided into shNC, shUSP20-1, and shUSP20-2 groups, and transfected with corresponding lentiviruses. Knockdown efficiency was verified by qPCR and WB. Cell proliferation, migration, and cell cycle distribution were assessed using CCK-8, colony formation, wound healing, Transwell assays, and flow cytometry, respectively. WB was used to detect the expression of epithelial-mesenchymal transition (EMT)-related transcription factors. Co-immunoprecipitation (CoIP) and ubiquitination assays were conducted to determine whether USP20 interacts with TWIST and regulates its expression via the ubiquitination pathway. Results: USP20 and TWIST mRNA levels were significantly upregulated in pancreatic cancer tissues (both P < 0.05), and their levels were negatively correlated with patient prognosis (both P < 0.05). USP20 protein was highly expressed in PANC1, SW1990, MIAPaca2, and BxPC3 cells (all P < 0.001). Knockdown of USP20 significantly inhibited the proliferation and migration of PANC1 and SW1990 cells (all P < 0.001). USP20 interacted with TWIST (P < 0.05 or P < 0.01) and stabilized TWIST expression by reducing its ubiquitination level (P < 0.01). Conclusion: USP20 is highly expressed in pancreatic cancer tissues and promotes pancreatic cancer cell proliferation and migration by stabilizing TWIST through deubiquitination. These findings suggest that USP20 may serve as a potential diagnostic and therapeutic target in the treatment of pancreatic cancer.
[Abstract] Objective: To investigate the expression of ubiquitin-specific protease 20 (USP20) in pancreatic cancer tissues and its role and molecular mechanism in the proliferation and migration of pancreatic cancer cells. Methods: The Cancer Genome Atlas (TCGA) database was used to analyze USP20 and TWIST family bHLH transcription factor (TWIST) expression in pancreatic cancer tissues. Kaplan-Meier curve analysis was used evaluate their correlation with patient prognosis. Normal pancreatic cells (HPNE) and pancreatic cancer cells (MIAPaca2, BxPC3, PANC1, SW1990, Aspc1) were routinely cultured, and USP20 protein expression was detected by Western blot (WB). PANC1 and SW1990 cells were divided into shNC, shUSP20-1, and shUSP20-2 groups, and transfected with corresponding lentiviruses. Knockdown efficiency was verified by qPCR and WB. Cell proliferation, migration, and cell cycle distribution were assessed using CCK-8, colony formation, wound healing, Transwell assays, and flow cytometry, respectively. WB was used to detect the expression of epithelial-mesenchymal transition (EMT)-related transcription factors. Co-immunoprecipitation (CoIP) and ubiquitination assays were conducted to determine whether USP20 interacts with TWIST and regulates its expression via the ubiquitination pathway. Results: USP20 and TWIST mRNA levels were significantly upregulated in pancreatic cancer tissues (both P < 0.05), and their levels were negatively correlated with patient prognosis (both P < 0.05). USP20 protein was highly expressed in PANC1, SW1990, MIAPaca2, and BxPC3 cells (all P < 0.001). Knockdown of USP20 significantly inhibited the proliferation and migration of PANC1 and SW1990 cells (all P < 0.001). USP20 interacted with TWIST (P < 0.05 or P < 0.01) and stabilized TWIST expression by reducing its ubiquitination level (P < 0.01). Conclusion: USP20 is highly expressed in pancreatic cancer tissues and promotes pancreatic cancer cell proliferation and migration by stabilizing TWIST through deubiquitination. These findings suggest that USP20 may serve as a potential diagnostic and therapeutic target in the treatment of pancreatic cancer.
JIANG Han
,
LIU Yao
,
WU Bibo
,
WANG Yu
,
ZHANG Jing
,
HU Yinxiang
,
OUYANG Weiwei
,
LU Bing
,
SU Shengfa
2025, 32(12):1262-1270.
Abstract:
[Abstract] Objective: To investigate the effect of high mobility group box-1 protein (HMGB1) neutralizing antibodies on radiationinduced lung injury in transplanted tumor-bearing mice. Methods: Twenty-five male C57BL/6 mice were randomly divided into five groups: control group, PD-1 inhibitor group, radiotherapy group, radiotherapy + PD-1 inhibitor group, and HMGB1 neutralizing antibody + PD-1 inhibitor + radiotherapy group, with five mice in each group. Subcutaneous transplantation of lung carcinoma LLC cells was performed on the right hind limb of each animal to establish the primary tumor, whilst subcutaneous transplantation of LLC cells on the left hind limb served as the secondary tumor. On day 28 of the experiment, animals were euthanized, and lung tissue and transplanted tumors were collected. Hematoxylin and eosin (H-E) staining and Masson's trichrome staining were performed to observe the pathological changes in the lung tissues of experimental mice. Immunohistochemistry (IHC) was used to detect the infiltration of CD4+ and CD8+ T lymphocytes in lung and transplanted tumor tissues. Enzyme-linked immunosorbent assay (ELISA) was used to examine the expression of TNF-α, TGF-β, and IL-6 in lung tissues. Results: Compared with the control and PD-1 inhibitor groups, the other three groups showed significantly reduced transplanted tumor volumes (P < 0.01 or P < 0.001), with HMGB1 neutralizing antibodies not further decreasing tumor volume. Similarly, compared with the control and PD-1 inhibitor groups, the inflammation scores and collagen volume fraction (CVF) in lung tissues were notably increased in the other three groups (P < 0.05, P < 0.01, P < 0.001, or P < 0.0001), and HMGB1 neutralizing antibodies partially inhibited the adverse effects of radiotherapy (P < 0.01 or P < 0.001). Compared to the control or PD-1 inhibitor groups, CD4+ T lymphocyte infiltration was significantly increased in the lung tissues of the other three groups, and HMGB1 neutralizing antibodies partially inhibited CD4+ T lymphocyte infiltration in lung tissue (P < 0.01). Moreover, in the transplanted tumor tissues, compared with the control or PD-1 inhibitor groups, the other three groups demonstrated significantly increased CD4+ and CD8+ T lymphocyte infiltration (all P < 0.001); however, HMGB1 neutralizing antibodies did not inhibit T cell infiltration in the transplanted tumor tissues. Compared with the control or PD-1 inhibitor groups, IL-6 expression in lung tissue was elevated and TGF-β expression was decreased in the other three groups (P < 0.05), and HMGB1 neutralizing antibodies had no significant effect on the expression of TNF-α, IL-6, or TGF-β in lung tissue. Conclusion: HMGB1 neutralizing antibodies may reduce the infiltration of inflammatory cells in the lungs, thereby alleviating lung inflammatory injury and fibrosis, without affecting the inhibition of transplanted tumor growth effects.
[Abstract] Objective: To investigate the effect of high mobility group box-1 protein (HMGB1) neutralizing antibodies on radiationinduced lung injury in transplanted tumor-bearing mice. Methods: Twenty-five male C57BL/6 mice were randomly divided into five groups: control group, PD-1 inhibitor group, radiotherapy group, radiotherapy + PD-1 inhibitor group, and HMGB1 neutralizing antibody + PD-1 inhibitor + radiotherapy group, with five mice in each group. Subcutaneous transplantation of lung carcinoma LLC cells was performed on the right hind limb of each animal to establish the primary tumor, whilst subcutaneous transplantation of LLC cells on the left hind limb served as the secondary tumor. On day 28 of the experiment, animals were euthanized, and lung tissue and transplanted tumors were collected. Hematoxylin and eosin (H-E) staining and Masson's trichrome staining were performed to observe the pathological changes in the lung tissues of experimental mice. Immunohistochemistry (IHC) was used to detect the infiltration of CD4+ and CD8+ T lymphocytes in lung and transplanted tumor tissues. Enzyme-linked immunosorbent assay (ELISA) was used to examine the expression of TNF-α, TGF-β, and IL-6 in lung tissues. Results: Compared with the control and PD-1 inhibitor groups, the other three groups showed significantly reduced transplanted tumor volumes (P < 0.01 or P < 0.001), with HMGB1 neutralizing antibodies not further decreasing tumor volume. Similarly, compared with the control and PD-1 inhibitor groups, the inflammation scores and collagen volume fraction (CVF) in lung tissues were notably increased in the other three groups (P < 0.05, P < 0.01, P < 0.001, or P < 0.0001), and HMGB1 neutralizing antibodies partially inhibited the adverse effects of radiotherapy (P < 0.01 or P < 0.001). Compared to the control or PD-1 inhibitor groups, CD4+ T lymphocyte infiltration was significantly increased in the lung tissues of the other three groups, and HMGB1 neutralizing antibodies partially inhibited CD4+ T lymphocyte infiltration in lung tissue (P < 0.01). Moreover, in the transplanted tumor tissues, compared with the control or PD-1 inhibitor groups, the other three groups demonstrated significantly increased CD4+ and CD8+ T lymphocyte infiltration (all P < 0.001); however, HMGB1 neutralizing antibodies did not inhibit T cell infiltration in the transplanted tumor tissues. Compared with the control or PD-1 inhibitor groups, IL-6 expression in lung tissue was elevated and TGF-β expression was decreased in the other three groups (P < 0.05), and HMGB1 neutralizing antibodies had no significant effect on the expression of TNF-α, IL-6, or TGF-β in lung tissue. Conclusion: HMGB1 neutralizing antibodies may reduce the infiltration of inflammatory cells in the lungs, thereby alleviating lung inflammatory injury and fibrosis, without affecting the inhibition of transplanted tumor growth effects.
2025, 32(12):1271-1279.
Abstract:
[Abstract] Objective: To evaluate the efficacy and safety of Pegylated Recombinant Human Granulocyte Colony-Stimulating Factor (PEG-rhG-CSF) combined with sintilimab and platinum-based chemotherapy in the treatment of advanced non-squamous non-small cell lung cancer (NSCLC). Methods: A prospective, randomized controlled study was conducted on 187 patients with stage Ⅳ nonsquamous NSCLC admitted to the Department of Oncology at Jinan Eighth People's Hospital from January 2020 to December 2021. The patients were randomly divided into an experimental group (PEG-rhG-CSF + sintilimab + pemetrexed + platinum; n = 94) or a control group (sintilimab + pemetrexed + platinum, n = 93) using a random number table method. All patients were followed for two years. Short-term clinical efficacy, progression-free survival (PFS), overall survival (OS), and treatment-related adverse reactions were compared between the two groups. Results: The objective response rate (ORR) in the experimental group was higher than that in the control group (61.63% [53/86] vs 45.35% [39/86], χ2 = 4.554, P = 0.032 8). The disease control rate (DCR) did not differ significantly between the two groups (87.21% [75/86] vs 81.40% [70/86], χ2 = 1.092, P = 0.079 1). The median progression-free survival (PFS) in the experimental group was significantly longer than that in the control group [10.6 months vs 9.1 months; HR = 0.72; χ2 = 3.899 8, P = 0.048 3]. The median overall survival (OS) in the experimental group was also significantly longer than that in the control group [not reached vs 22.6 months; HR = 0.63; χ2 = 4.7716, P = 0.028 9]. Consistent OS benefits (all HR < 1) were observed in the predefined subgroup analyses, including age < 65 years (yes or no), gender, smoking history (yes or no), PD-L1 TPS ≥ 1% (yes or no), platinumbased drugs (cisplatin or carboplatin), and ECOG PS score (0 or 1). The incidence of neutropenia was significantly lower in the experimental group than that in the control group (P < 0.000 1), while the incidence of fever was significantly higher (P = 0.045 1). No significant differences were observed between the two groups in nausea, anemia, fatigue, constipation, diarrhea, decreased appetite, vomiting, cough, dyspnea, peripheral edema, muscle pain, rash, thrombocytopenia, hypothyroidism, immune pneumonitis, or immunerelated colitis (all P > 0.05). Conclusion： The combination of PEG-rhG-CSF with sintilimab, pemetrexed, and platinum-based chemotherapy in advanced non-squamous NSCLC patients may improve short-term clinical efficacy and long-term survival, reduce the incidence of neutropenia, and maintain controllable safety.
[Abstract] Objective: To evaluate the efficacy and safety of Pegylated Recombinant Human Granulocyte Colony-Stimulating Factor (PEG-rhG-CSF) combined with sintilimab and platinum-based chemotherapy in the treatment of advanced non-squamous non-small cell lung cancer (NSCLC). Methods: A prospective, randomized controlled study was conducted on 187 patients with stage Ⅳ nonsquamous NSCLC admitted to the Department of Oncology at Jinan Eighth People's Hospital from January 2020 to December 2021. The patients were randomly divided into an experimental group (PEG-rhG-CSF + sintilimab + pemetrexed + platinum; n = 94) or a control group (sintilimab + pemetrexed + platinum, n = 93) using a random number table method. All patients were followed for two years. Short-term clinical efficacy, progression-free survival (PFS), overall survival (OS), and treatment-related adverse reactions were compared between the two groups. Results: The objective response rate (ORR) in the experimental group was higher than that in the control group (61.63% [53/86] vs 45.35% [39/86], χ2 = 4.554, P = 0.032 8). The disease control rate (DCR) did not differ significantly between the two groups (87.21% [75/86] vs 81.40% [70/86], χ2 = 1.092, P = 0.079 1). The median progression-free survival (PFS) in the experimental group was significantly longer than that in the control group [10.6 months vs 9.1 months; HR = 0.72; χ2 = 3.899 8, P = 0.048 3]. The median overall survival (OS) in the experimental group was also significantly longer than that in the control group [not reached vs 22.6 months; HR = 0.63; χ2 = 4.7716, P = 0.028 9]. Consistent OS benefits (all HR < 1) were observed in the predefined subgroup analyses, including age < 65 years (yes or no), gender, smoking history (yes or no), PD-L1 TPS ≥ 1% (yes or no), platinumbased drugs (cisplatin or carboplatin), and ECOG PS score (0 or 1). The incidence of neutropenia was significantly lower in the experimental group than that in the control group (P < 0.000 1), while the incidence of fever was significantly higher (P = 0.045 1). No significant differences were observed between the two groups in nausea, anemia, fatigue, constipation, diarrhea, decreased appetite, vomiting, cough, dyspnea, peripheral edema, muscle pain, rash, thrombocytopenia, hypothyroidism, immune pneumonitis, or immunerelated colitis (all P > 0.05). Conclusion： The combination of PEG-rhG-CSF with sintilimab, pemetrexed, and platinum-based chemotherapy in advanced non-squamous NSCLC patients may improve short-term clinical efficacy and long-term survival, reduce the incidence of neutropenia, and maintain controllable safety.
HE Yuan
,
ZHOU Xiaoxian
,
ZHANG Yan
,
SHI Ruifang
,
WANG Jing
,
WANG Zixuan
,
WANG Zhongda
,
ZHU Yue
,
SHU Yan
,
WANG Jing
,
YAO Lu
,
FU Gongbo
,
LEI Zengjie
,
JIA Shaochang
,
JIANG Longwei
2025, 32(12):1280-1284.
Abstract:
[Abstract] Objective: To retrospectively analyze the clinical efficacy and safety of DC-CIK loaded with different antigens in the treatment of malignant melanoma (MM). Methods: Peripheral blood mononuclear cells were collected from 42 melanoma patients admitted to the Qinhuai Medical Area of Eastern Theater General Hospital between October 2012 and December 2024. DCs and CIKs were induced and cultured in vitro in the laboratory. Patients were divided into a polypeptide group and a cell group based on their HLA-A2 expression. The polypeptide group was loaded with a mixed peptide cocktail, and the cell group was loaded with lysate from the tumor cell A375. After maturation, DC and CIK were reinfused into the patients. The objective clinical response and survival period of the two groups of patients were compared. Peripheral blood lymphocyte subsets of the two groups of patients were detected before and after treatment, and adverse reactions after reinfusion were observed. Results: Among the 42 patients, 0 achieved CR; 0 achieved PR; 31 had SD, and 11 had PD. Specifically, in the peptide group, 18 had SD and 6 had PD; in the cell group, 13 had SD and 5 had PD. The disease control rate (DCR) was 75% in the polypeptide group and 72.2% in the cell group. Among the 42 patients, 12 died (4 in the cell group, 8 in the polypeptide group). The 1-year OS rate was 76.6% in the polypeptide group vs 66.7% in the cell group; the 2-year survival rate was 43.8% vs 66.7%; the 3-year survival rate was 43.8% .33.3%. The 3-year OS rate of the polypeptide group was slightly higher than that of the cell group, with no significant difference between the two groups (P = 0.445). Lymphocyte subsets of the two groups of MM patients before and after treatment showed no significant difference（P > 0.05）. No severe adverse reactions occurred in either group. Conclusion: Both tumor cell-loaded DC-CIK therapy and mixed polypeptide-loaded DC-CIK therapy are safe for MM patients and can provide clinical benefits. However, there are no significant differences in short-term efficacy, long-term survival, or immune responses between the two methods.
[Abstract] Objective: To retrospectively analyze the clinical efficacy and safety of DC-CIK loaded with different antigens in the treatment of malignant melanoma (MM). Methods: Peripheral blood mononuclear cells were collected from 42 melanoma patients admitted to the Qinhuai Medical Area of Eastern Theater General Hospital between October 2012 and December 2024. DCs and CIKs were induced and cultured in vitro in the laboratory. Patients were divided into a polypeptide group and a cell group based on their HLA-A2 expression. The polypeptide group was loaded with a mixed peptide cocktail, and the cell group was loaded with lysate from the tumor cell A375. After maturation, DC and CIK were reinfused into the patients. The objective clinical response and survival period of the two groups of patients were compared. Peripheral blood lymphocyte subsets of the two groups of patients were detected before and after treatment, and adverse reactions after reinfusion were observed. Results: Among the 42 patients, 0 achieved CR; 0 achieved PR; 31 had SD, and 11 had PD. Specifically, in the peptide group, 18 had SD and 6 had PD; in the cell group, 13 had SD and 5 had PD. The disease control rate (DCR) was 75% in the polypeptide group and 72.2% in the cell group. Among the 42 patients, 12 died (4 in the cell group, 8 in the polypeptide group). The 1-year OS rate was 76.6% in the polypeptide group vs 66.7% in the cell group; the 2-year survival rate was 43.8% vs 66.7%; the 3-year survival rate was 43.8% .33.3%. The 3-year OS rate of the polypeptide group was slightly higher than that of the cell group, with no significant difference between the two groups (P = 0.445). Lymphocyte subsets of the two groups of MM patients before and after treatment showed no significant difference（P > 0.05）. No severe adverse reactions occurred in either group. Conclusion: Both tumor cell-loaded DC-CIK therapy and mixed polypeptide-loaded DC-CIK therapy are safe for MM patients and can provide clinical benefits. However, there are no significant differences in short-term efficacy, long-term survival, or immune responses between the two methods.
2025, 32(12):1285-1291.
Abstract:
[摘 要] 伴随高通量检测技术的发展，大量疾病靶点被发掘，但其中大部分致癌突变均不是传统的小分子抑制剂的直接作用 靶点。协同致死效应是一种新兴的肿瘤精准治疗策略，通过靶向抑制补偿性基因，选择性诱导肿瘤细胞死亡而不损伤正常组织， 成为实现精准治疗的理想途径。本文就协同致死效应概念的提出与演变、相关筛选技术发展、分子机制探索及不同类型肿瘤的 临床治疗策略等方面进行综述，并探讨了当前面临的挑战和未来的研究方向。
[摘 要] 伴随高通量检测技术的发展，大量疾病靶点被发掘，但其中大部分致癌突变均不是传统的小分子抑制剂的直接作用 靶点。协同致死效应是一种新兴的肿瘤精准治疗策略，通过靶向抑制补偿性基因，选择性诱导肿瘤细胞死亡而不损伤正常组织， 成为实现精准治疗的理想途径。本文就协同致死效应概念的提出与演变、相关筛选技术发展、分子机制探索及不同类型肿瘤的 临床治疗策略等方面进行综述，并探讨了当前面临的挑战和未来的研究方向。
2025, 32(12):1292-1297.
Abstract:
[摘 要] 成人原发性眼内恶性肿瘤中，葡萄膜黑色素瘤最为多见，有50%的患者因转移离世，其中有90%转移至肝脏部位，转 移后中位生存期不足12个月，其免疫治疗难题是由独特的时空异质性免疫逃逸引发的，即原发灶依靠血—视网膜屏障和免疫调 节形成的免疫豁免微环境，从而抑制自然杀伤细胞活性并导致T细胞功能下降；转移瘤由于染色体异常与免疫抑制体系导致“免 疫荒漠”表型显现等。目前，免疫检查点抑制剂客观缓解比例不足8%，抗原异质性加上免疫抑制微环境导致肿瘤疫苗失去功效， 本文将机制研究与临床数据相结合，构建联合表观遗传干预及精准细胞疗法的策略，为逆转免疫逃逸提供新方向。
[摘 要] 成人原发性眼内恶性肿瘤中，葡萄膜黑色素瘤最为多见，有50%的患者因转移离世，其中有90%转移至肝脏部位，转 移后中位生存期不足12个月，其免疫治疗难题是由独特的时空异质性免疫逃逸引发的，即原发灶依靠血—视网膜屏障和免疫调 节形成的免疫豁免微环境，从而抑制自然杀伤细胞活性并导致T细胞功能下降；转移瘤由于染色体异常与免疫抑制体系导致“免 疫荒漠”表型显现等。目前，免疫检查点抑制剂客观缓解比例不足8%，抗原异质性加上免疫抑制微环境导致肿瘤疫苗失去功效， 本文将机制研究与临床数据相结合，构建联合表观遗传干预及精准细胞疗法的策略，为逆转免疫逃逸提供新方向。
2025, 32(12):1298-1303.
Abstract:
[摘 要] DNA复制失调是导致肿瘤细胞异常增殖的重要因素之一，靶向DNA复制调控是肿瘤治疗的重要方向之一。色氨酸天冬氨酸重复序列和高迁移率族蛋白盒DNA结合蛋白1（WDHD1）作为复制体复合物的关键组分蛋白，以三聚体形式在DNA复 制过程中发挥多层次的调控作用。WDHD1作为肿瘤促进因子，被发现在多种肿瘤类型中异常高表达，并通过影响不同靶点以及 信号通路影响肿瘤细胞增殖。本文综述了WDHD1的蛋白结构特征、生物学功能，并重点讨论近年来其在肿瘤发生发展中的分子 机制及作为靶向抑制剂的研究进展。
[摘 要] DNA复制失调是导致肿瘤细胞异常增殖的重要因素之一，靶向DNA复制调控是肿瘤治疗的重要方向之一。色氨酸天冬氨酸重复序列和高迁移率族蛋白盒DNA结合蛋白1（WDHD1）作为复制体复合物的关键组分蛋白，以三聚体形式在DNA复 制过程中发挥多层次的调控作用。WDHD1作为肿瘤促进因子，被发现在多种肿瘤类型中异常高表达，并通过影响不同靶点以及 信号通路影响肿瘤细胞增殖。本文综述了WDHD1的蛋白结构特征、生物学功能，并重点讨论近年来其在肿瘤发生发展中的分子 机制及作为靶向抑制剂的研究进展。
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Chinese Journal Of Cancer Biotheray ® 2026 All Rights Reserved
Supported by:Beijing E-Tiller Technology Development Co., Ltd.
Chinese Journal Of Cancer Biotheray ® 2026 All Rights Reserved
Supported by:Beijing E-Tiller Technology Development Co., Ltd.