The TIM-3/Gal-9 Pathway: A Promising Therapeutic Target for Regulation of Immune Checkpoint in Rheumatoid ArthritisSur, Pramanik
Curr Rheumatol Rev (2025)
Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune ailment that is marked by persistent synovial joint inflammation, which causes joint destruction and other systemic consequences. The immune system is equipped with a wide range of effector mechanisms that are capable of inflicting severe harm on pathogens that invade it, as well as inflicting severe harm on the body itself. The immune system must carefully regulate itself to avoid such damage to host tissues and restore equilibrium following an inflammatory response. In the peripheral immune system, the immune cell responses are regulated by a balance of positive and negative signals that are sent to effector cells to adjust them to their environment. The identification of immunological checkpoints has opened up new avenues for studying and perhaps modifying immune responses in the context of RA pathogenesis. T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3), a member of the TIM family, has emerged as a major regulator in immune checkpoint pathways, with several studies on its various functions in immunological homeostasis and autoimmune disorders. This review narrates the critical function of TIM-3 in the control of immunological checkpoints in rheumatoid arthritis also the potential role of TIM-3/GAL-9 signalling as a therapeutic target for the development of a new class of immunotherapeutic agents for the treatment of RA.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
NAT10 promotes radiotherapy resistance in non-small cell lung cancer by regulating KPNB1-mediated PD-L1 nuclear translocationZhu, Lu, Cheng
Open Life Sci (2025) 20 (1), 20251065
Abstract: Radiotherapy (RT) resistance in non-small cell lung cancer (NSCLC) is a significant contributor to tumor recurrence. NAT10, an enzyme that catalyzes ac4C RNA modification, has an unclear role in RT resistance. This study aimed to explore the function of NAT10 in RT resistance in NSCLC. RT-resistant NSCLC cell lines (PC9R and A549R) were established through repeated irradiation. The impact of NAT10 on cellular immunity was evaluated by measuring immune cell populations, cytotoxicity levels, and markers of cell dysfunction. Results demonstrated elevated levels of ac4C and NAT10 in RT-resistant cells. Knockdown of NAT10 suppressed cell proliferation and enhanced immune function in PC9R and A549R cells by upregulating TNF-α and IFN-γ while downregulating PD-1 and TIM-3. Mechanistically, RT resistance in NSCLC was mediated by NAT10-dependent ac4C modification of KPNB1. Furthermore, KPNB1 facilitated PD-L1 nuclear translocation, promoting immune escape in RT-resistant NSCLC cells. Overexpression of KPNB1 enhanced cell proliferation but impaired immune function in RT-resistant NSCLC cells. In conclusion, this study demonstrates that NAT10 upregulates KPNB1 expression through ac4C modification, thereby promoting RT resistance in NSCLC via PD-L1 nuclear translocation. These findings reveal a novel mechanism underlying RT resistance in NSCLC.© 2025 the author(s), published by De Gruyter.
A novel peptide targeting CCR7 inhibits tumor cell lymph node metastasisSun, Qian, Qiu
et alCancer Immunol Immunother (2025) 74 (5), 153
Abstract: Lymph nodes are the most common metastasis sites for tumor cells, which are intimately linked to patient prognosis. It has been reported that cancer cells can upregulate CC Chemokine Receptor 7 (CCR7) expression and hijack its normal functions, enabling them to migrate along the gradient of CCL19 and CCL21 toward the lymph nodes and colonies as the initial stage of distant metastasis. In tumor patients, the metastatic tumor in the lymph nodes exhibited higher expression of CCR7, as well as inhibitory immune checkpoints PD-1, LAG-3, and TIM-3 compared to the primary tumors with the analysis of TCGA and GEO databases. Also, in mouse tumor model, tumor cells with elevated CCR7 expression were more susceptible to develop popliteal lymph node metastasis. Subsequently, we successfully identified a CCR7 binding peptide TC6 by phage display biopanning, which specifically blocks the interaction of CCR7/CCL19 and CCR7/CCL21. Further, the D-amino acids were introduced to substitute the N- and C-terminus of TC6 peptide to obtain the proteolysis-resistant TC6-D3 peptide, which decreased tumor cell migration in vitro via ERK1/2 pathway and inhibited tumor growth and lymph nodes metastasis in vivo, as well as effectively restored T cells cytotoxicity in both primary tumors and lymph nodes. In conclusion, CCR7 promoted tumor cell metastasis to lymph node and inhibited the anti-tumor immune responses in lymph nodes. Specific blockade of the CCR7 pathway with TC6-D3 peptide can significantly reduce lymph node tumor burden, promoting CD8+ T cell infiltration in primary tumors, meanwhile, enhancing anti-tumor immune responses in lymph nodes.© 2025. The Author(s).
[Effect of moxibustion combined with chemotherapy on immune checkpoints in tumor tissue of breast cancer-bearing mice]Zhang, Gao, Zhang
et alZhen Ci Yan Jiu (2025) 50 (3), 319-326
Abstract: To observe the effects of moxibustion combined with chemotherapy on immune checkpoints including programmed cell death protein 1 (PD-1), T cell immunoglobulin domain and mucin domain (TIM-3) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in the tumor tissue of breast cancer-bearing mice, so as to explore the effect and mechanisms of moxibustion combined with chemotherapy on breast cancer.Forty BALB/c female mice were randomly divided into model, chemotherapy, moxibustion and combination groups, with 10 mice in each group. 4T1 tumor cells were inoculated into the fat pad under the left fourth nipple of the mice to establish the breast cancer-bearing mice model. The chemotherapy group was injected intraperitoneally with doxorubicin (DOX) solution at 2.5 mg/kg once every 3 days;the moxibustion group received bilateral "Zusanli" (ST36) moxibustion with 2 moxa cones per point, treated every 2 days;the combination group received both DOX injection and moxibustion intervention. The above interventions lasted for 21 days. The body weight and tumor volume of the mice were recorded daily. HE staining was used to observe tumor tissue pathological morphology. Immunohistochemistry and Western blot were used to detect the positive expression and protein expression levels of PD-1, TIM-3, and CTLA-4 in the tumor tissue.Compared with the model group after intervention, the body weight was increased (P<0.01, P<0.05), the tumor volume was decreased (P<0.01), the pathological morphology of tumor tissue showed varying degrees of tumor cells degeneration, and the positive expression and protein expression levels of PD-1, TIM-3, and CTLA-4 in tumor tissue were decreased (P<0.01, P<0.05) of mice in the chemotherapy, moxibustion and combination groups. Compared with the chemotherapy group, the body weight of mice in the moxibustion group was higher (P<0.01);the tumor volume of mice in the combination group was smaller (P<0.01);the positive expression and protein expression levels of PD-1, TIM-3, and CTLA-4 were further reduced (P<0.01, P<0.05) of mice in the moxibustion and combination groups. Compared with the moxibustion group, the body weight was decreased (P<0.01), the tumor volume was smaller (P<0.01), the degree of tumor cell degeneration was higher, and the positive expression and protein expression levels of PD-1, TIM-3, and CTLA-4 were decreased (P<0.01) of mice in the combination group.Moxibustion combined with chemotherapy shows more significant effects in inhibiting tumor growth in breast cancer-bearing mice compared to moxibustion or chemotherapy alone. It reduces the expression of PD-1, TIM-3, and CTLA-4 in tumor tissues, suggesting that lowering immune checkpoint expression levels may be one of the mechanisms by which moxibustion combined with chemotherapy drugs treats tumors.
膜杰作
Star Staining
