Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with morbidity and mortality driven by late diagnosis, a dense desmoplastic stroma, and resistance to conventional therapies. Over sequential therapeutic eras, treatment has progressed from early cytotoxic agents to metabolism-directed strategies. A central feature of PDAC biology is extensive metabolic reprogramming, largely controlled by the Kirsten rat sarcoma viral oncogene homologue (KRAS) protein, which promotes aerobic glycolysis, glutamine utilization, and mitochondrial oxidative phosphorylation to sustain tumor growth under nutrient-limiting conditions. Accordingly, therapeutic efforts have increasingly focused on exploiting these metabolic dependencies, including inhibitors of glycolysis, glutaminase, and mitochondrial complex I, which have shown encouraging results in preclinical studies. Constitutively elevated autophagy-lysosomal flux provides PDAC cells with the capacity for nutrient recycling and supports immune evasion by promoting the neighbor of BRCA1 gene 1 (NBR1) protein-dependent degradation of major histocompatibility complex class I (MHC-I). Although inhibition of autophagy with hydroxychloroquine and related lysosomal inhibitors has provided proof of concept, their limited specificity has motivated the development of more selective approaches, such as Unc-51-like autophagy activating kinase 1 (ULK1) inhibitors and selective autophagy receptor-directed strategies. Emerging combination regimens that integrate autophagy blockade with KRAS/extracellular signal-regulated kinase (ERK) pathway inhibition, metabolic stress, or immune checkpoint blockade may help overcome chemoresistance and enhance anti-tumor immunity. Together, these advances underscore the therapeutic promise of targeting metabolic plasticity and autophagy in PDAC and lay the groundwork for rational next-generation combination strategies.

Cancer is one of the diseases with high incidence and mortality rates. As a result, many studies have led to the development of therapeutic agents such as immune checkpoint inhibitors. However, the research on cancer treatment is still essential because of problems including drug resistance, genetic variation among patients, and drug toxicity. To address these problems, several candidate chemicals, including phytochemicals, have been studied for cancer treatment. Phytochemicals exhibit a variety of biochemical and physiological functions in the body and have been studied as having lower toxicity than synthetic chemicals. These properties have led to research into their potential as anti-cancer agents as well as their therapeutic applications for a variety of other diseases. The structural diversity of phytochemicals leads to considerable variations in their mechanisms of action. Therefore, it is important to understand the mechanism of action of each phytochemical when studying phytochemicals. Tangeretin (TAN) is mainly extracted from citrus fruits and is characterized by the presence of a methyl group. The presence of a methyl group in TAN is thought to enhance its intracellular uptake and confer greater resistance to degradation compared with other phytochemicals. Previous studies on the use of TAN in cancer treatment have mainly focused on its ability to induce oxidative stress as the primary anti-cancer mechanism. In addition, some studies suggest that TAN also exerts various other anti-cancer effects, such as upregulating tumor suppressor proteins, inducing apoptosis, and reducing the proportion of cancer stem cells (CSCs). This review highlights the anti-cancer effects of TAN in different cancers and aims to provide data to support future research.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality, and many patients show limited durable responses to systemic therapy. Rivoceranib (apatinib), an oral vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitor, has clinical activity in advanced HCC, particularly with PD-1 blockade, yet incomplete responses and resistance persist. Because VEGFR2 is expressed mainly in tumor-associated vasculature and is low in malignant hepatocytes, how rivoceranib acts beyond VEGFR2, and how this tumor-cell-intrinsic activity might be amplified, remains undefined. Reasoning that intracellular Ca²⁺ overload can trigger tumor-cell death, we screened cannabinoids as combination partners and identified the non-psychoactive phytocannabinoid cannabigerol (CBG) as the strongest enhancer of rivoceranib-induced growth inhibition. CBG synergized with rivoceranib in HCC cells and potentiated its anti-tumor activity in xenograft tumors. Transcriptomic profiling revealed apoptosis- and ER stress-related programs, including CHOP induction, together with suppression of FOXM1-centered mitotic cell-cycle programs. The combination induced sustained intracellular Ca²⁺ accumulation, and Ca²⁺ blockade reduced apoptosis, restored cell-cycle regulators, and reactivated PI3K–AKT–mTOR signaling. Unexpectedly, this Ca²⁺ signal proved receptor-independent: TRPV1/TRPV2 antagonists blocked resiniferatoxin-induced Ca²⁺ influx but not the CBG–rivoceranib-induced Ca²⁺ increase, and TRPV knockdown likewise left the combination response intact. Instead, ER stress inhibition attenuated Ca²⁺ accumulation and cytotoxicity, placing ER stress upstream of the lethal Ca²⁺ signal. Downstream, E2F1 emerged as the proximal regulator of FOXM1, and E2F1 re-expression restored FOXM1 and partially rescued cell-cycle progression. Together, CBG converts rivoceranib into a tumor-cell-intrinsic therapy through a receptor-independent, ER stress-dependent Ca²⁺ program that collapses the E2F1–FOXM1 axis.

Breast cancer is one of the most prevalent cancers among women, often attributed to genetic mutations, hormonal imbalances, and lifestyle factors. The compound benzo[α]pyrene (B[α]P) is commonly found in emissions and fumes from industrial processes and cigarette smoke. Punicalagin (PCG), a polyphenolic compound in pomegranates, is reported to have antioxidant, anti-inflammatory, anti-cancer, and antiviral activities. In this study, we aimed to determine whether B[α]P induced toxicity in breast cancer cells and to assess the role of PCG in mitigating this toxicity. The water-soluble tetrazolium salt (WST) assay showed that exposure of MDA-MB-231 and MCF-7 cells to B[α]P at 1–32 µM decreased their viability. B[α]P also resulted in the decrease of the mitochondrial membrane potential in both cell lines. The change in mitochondrial reactive oxygen species levels was confirmed using MitoSOX™ staining of MDA-MB-231 and MCF-7 cells, and the level of red fluorescence increased upon exposure to B[α]P compared to the control group. In the scratch wound healing and transwell migration assays, B[α]P induced migration of MDA-MB-231 cells, which was mitigated by PCG. Furthermore, there was an increase in the N-cadherin expression and a decrease in the E-cadherin expression on exposure to B[α]P. However, PCG reversed this trend. Our findings suggest that PCG mitigates B[α]P-induced mitochondrial dysfunction, oxidative stress, and epithelial-mesenchymal transition, thereby reversing B[α]P’s pro-tumorigenic effects in breast cancer cells.

Ovarian cancer remains a leading cause of gynecologic cancer-related mortality and is frequently associated with therapeutic resistance. Punicalagin (PCG), a pomegranate-derived polyphenol, has demonstrated anticancer activity in multiple tumor models, however, its effects in ovarian cancer require further clarification. This study evaluated the anti-proliferative and anti-migratory effects of PCG in two biologically distinct ovarian cancer cell lines, OVCAR-3 and SKOV-3. PCG treatment (6.25-200 µM) significantly reduced cell viability and colony formation in a dose- and time-dependent manner. Migration-associated behaviors were suppressed in wound-healing and transwell assays, accompanied by modulation of epithelial-mesenchymal transition markers, including increased E-cadherin and decreased N-cadherin expression. PCG increased reactive oxygen species (ROS) levels and reduced mitochondrial membrane potential in both cell lines. Annexin V/propidium iodide analysis demonstrated increased apoptotic cell populations, with elevated BAX expression. Autophagy-related changes, including LC3-I to LC3-II conversion and acridine orange-positive vesicles, were observed in OVCAR-3 cells but not in SKOV-3 cells. Collectively, these findings indicate that PCG exerts anti-proliferative and pro-apoptotic effects in ovarian cancer cells and is associated with oxidative stress and mitochondrial dysfunction. Further studies are required to define the mechanistic contribution of ROS and autophagy and to evaluate translational relevance in vivo.

Background/Objectives: Gastric cancer remains a leading cause of cancer-related mortality worldwide, highlighting the need for novel therapeutic strategies. Drug repositioning offers a cost-effective approach by identifying new therapeutic applications for clinically approved drugs. Fluphenazine (FPZ), a dopamine receptor D2 antagonist used as an antipsychotic drug, has demonstrated anticancer activity; however, its effects on gastric cancer remain unclear. Methods: This study investigated the anticancer effects of FPZ alone and in combination with cisplatin (DDP) in gastric cancer. Results: In MKN-45 cells, viability was 100%, 101.16%, 61.26%, and 53.12% in the control, FPZ, DDP, and combination groups, respectively; the corresponding values in AGS cells were 100%, 84.95%, 89.94%, and 73.94%. FPZ also inhibited migration and induced apoptosis, while combined treatment increased cytosolic and mitochondrial reactive oxygen species levels and mitochondrial stress. Furthermore, FPZ reduced IL-6 and IL-8 expression and attenuated DDP-induced inflammatory responses. In the mouse xenograft model, the tumor volumes were 1233.65, 1115.75, 768.88, and 309.44 mm3 in the control, FPZ, DDP, and combination groups, respectively. Conclusions: These findings support the potential of FPZ as a repurposed anticancer agent for gastric cancer, particularly in combination with DDP.

Cervical cancer is the fourth most common cancer and the fourth leading cause of cancer‑related mortality among women worldwide. Tangeretin (TAN), a polymethoxylated flavonoid derived from citrus fruit peel, exhibits relatively high structural stability due to its methoxy groups and exerts anticancer effects in various malignancies, including lung, liver and breast cancer. However, to the best of our knowledge, the anticancer effects of TAN in cervical cancer remain insufficiently explored. The present study investigated the mechanisms underlying the anticancer effects of TAN on the CaSki cervical cancer cell line. Cell viability was evaluated using the EZ‑Cytox cell viability assay. The colony formation and cell cycle arrest assays demonstrated that TAN inhibited cell proliferation by inducing G1 phase arrest. The wound‑healing and Transwell migration assays demonstrated that TAN could reduce the migratory ability of CaSki cells, and the Annexin V/propidium iodide staining assay revealed that TAN increased the apoptotic cell population. Mitochondrial reactive oxygen species (ROS) were identified using MitoSOX™ staining and the mitochondrial membrane potential (MMP) was detected using JC‑1 staining. The findings of these assays suggested that TAN could increase mitochondrial ROS levels and decrease mitochondrial MMP in CaSki cells. Western blot analysis showed that TAN upregulated the protein expression levels of E‑cadherin and Bax. In addition, TAN restored the tumor suppressor protein p53. Collectively, these findings suggested that may exhibit anticancer activity in CaSki cells.

While the prognosis of thyroid cancer is generally favorable effective therapeutic options remain limited for its advanced or metastatic stages. In this study, we investigated the anti-cancer effects of amiodarone, a widely prescribed anti-arrhythmic agent, in SNU-790 human thyroid cancer cells. Cell viability and cytotoxicity were evaluated using the water-soluble tetrazolium salt-8 assay, which demonstrated a concentration-dependent reduction in cell viability following amiodarone treatment, and the half-maximal inhibitory concentration value was determined accordingly. Flow cytometric analysis revealed that amiodarone induced G1-phase cell-cycle arrest, indicating suppression of thyroid cancer cell proliferation. In addition, a trans-well migration assay showed that amiodarone significantly inhibited cell migration in a concentration-dependent manner, suggesting a potential anti-metastatic effect. Intracellular and mitochondrial reactive oxygen species levels were assessed using 2’,7’-dichlorofluorescein diacetate and MitoSOX™ Red staining, respectively, and both were increased in the amiodarone-treated groups. Additionally, mitochondrial membrane potential was evaluated using JC-10 staining, which revealed a significant decrease. Furthermore, the apoptotic cell population was evaluated by Annexin V/propidium iodide staining, which demonstrated a significant increase in the induction of apoptosis in amiodarone-treated cells. Autophagic responses were further examined by acridine orange staining, which revealed an increase in acidic vesicular organelles, and Western blot analysis confirmed the accumulation of microtubule-associated protein 1 light chain 3B, indicating activation of autophagy in the SNU-790 cells. In conclusion, this study confirmed that amiodarone inhibits the proliferation and migration of thyroid cancer cells and induces apoptosis. Furthermore, we observed that amiodarone induces biochemical changes, including activation of autophagy and mitochondrial dysfunction, suggesting its potential as a repositioned therapeutic agent for thyroid cancer.

Endometrial cancer (EC) has become an increasing clinical concern as the incidence is rising, and treatment options available for advanced disease or recurrent disease are limited. In the present study, the anticancer potential of punicalagin (PCG), a natural ellagitannin polyphenol that comes from pomegranate, was characterized using both in vitro and in vivo models in EC. Two EC cell lines (Ishikawa and SNU‑539) treated with increasing doses of PCG showed dose‑dependent inhibition of cell proliferation and demonstrated a decrease in colony formation. PCG inhibited Transwell migration and an increase in E‑cadherin expression, indicating an inhibition of epithelial‑mesenchymal transition. Further experimental work characterized the mechanisms by which PCG acted and revealed that it decreased the mitochondrial membrane potential and subsequently increased levels of reactive oxygen species, which led to apoptosis as shown by increased BAX expression and Hoechst/PI staining. In addition, PCG showed signs of autophagy, especially in the Ishikawa cells, as indicated by increased levels of LC3‑IIB and the formation of autophagic vacuoles. In vivo studies using a xenograft mouse model showed that treatment with PCG significantly reduced tumor volume and weight, whereas body weight was not significantly affected, thus highlighting strong anticancer efficacy coupled with very low toxicity. Overall, the present study highlights PCG as a promising natural compound with multitarget anticancer activity against EC and warrants further preclinical and clinical research as a potential treatment option.

Glioblastoma (GBM) is a highly aggressive and lethal brain tumor characterized by metabolic reprogramming and epigenetic dysregulation. In GBM, the expression levels of Enhancer of Zeste Homolog 2 (EZH2) and dipeptidyl peptidase 4 (DPP4) are inversely correlated, significantly influencing tumor progression. To investigate these reports, the therapeutic potential of digitoxin, a plant-derived bioactive glycoside, was studied in combination with the chemotherapeutic agents temozolomide (TMZ) or romidepsin. We evaluated the EZH2-DPP4 axis and pro-apoptotic signaling using qPCR, western blot, and ELISA. The synergistic effects were assessed through cell viability assays, flow cytometry, and an orthotopic xenograft mouse model utilizing 18F-FDG PET imaging. Digitoxin effectively downregulated EZH2 while restoring DPP4 expression, thereby inhibiting tumor cell growth and enhancing apoptosis. Notably, the combination therapy effectively inhibited tumor progression and reduced tumor burden in vivo, resulting in significantly prolonged survival. Consistent effects were observed in EZH2-knockdown cells, confirming that digitoxin targets the EZH2-DPP4 pathway. These findings suggest that digitoxin acts as a novel epigenetic-regulatory agent, representing a promising integrative medicine and therapeutic strategy to overcome chemoresistance in GBM management.

Objectives: Progesterone (P4) is believed to inhibit breast cancer growth, but its role in counteracting estrogen (E2)-driven progression remains unclear. This study aimed to investigate the inhibitory effect of P4 on E2-induced cell proliferation, migration, and invasion in Estrogen receptor (ER)+/progesterone receptor (PR)+ breast cancer cells by examining its regulatory role in the epithelial-mesenchymal transition (EMT). Methods: ER and PR-positive MCF-7 clonal variant (MCF-7 CV) breast cancer cells were treated with E2 and co-treated with various concentrations of P4. The effects on cell proliferation, migration, and invasion were assessed. The expression of key EMT markers (E-cadherin, N-cadherin, vimentin), transcription factors (Snail, Slug), and apoptosis-related genes (p53, B-cell lymphoma 2 [BCL-2], BCL2-associated X [BAX]) were analyzed. Results: P4 significantly inhibited E2-induced cell proliferation in a dose-dependent manner. In the presence of E2, P4 treatment reversed EMT characteristics by increasing E-cadherin while decreasing N-cadherin, vimentin, Snail, and Slug. Consequently, P4 inhibited E2-stimulated cell migration and invasion. Furthermore, P4 treatment promoted apoptosis by upregulating BAX and p53 and downregulating BCL-2. Conclusion: Progesterone can counteract estrogen-driven breast cancer progression in ER+/PR+ cells by inhibiting proliferation, reversing the EMT process, and inducing apoptosis. These findings provide mechanistic insight into the protective role of PR signaling in breast cancer.

Melanoma is a highly aggressive form of cancer that occurs due to the malignant transformation of melanocytes. Despite the availability of a variety of therapeutic options, melanoma treatment remains a significant challenge and new approaches are constantly being explored. In this study, we evaluated self-amplifying mRNA (saRNA)based melanoma vaccine candidates targeting Melan-A, a melanoma-associated antigen (MAA), and assessed the immunogenicity and efficacy. The candidates were formulated with lipid inorganic nanoparticles (LIONs) and administered intramuscularly into mice. The immunogenicity was evaluated by enzyme-linked immunosorbent spot (ELISpot) assay and emzyme-linked immunoassay (ELISA). The results showed that one of the candidates, LS2-Melan-A (TM+), namely saMelan-A/LION, triggered the humoral immune response by producing immunoglobulin G (IgG) antibodies specific to Melan-A, rather than T cell-mediated immunity. Further studies were conducted to assess the therapeutic and preventive efficacy against melanoma using the B16F10 mouse melanoma model. In a therapeutic efficacy study, significant suppression of tumor growth was observed in the saMelan-A/LION administered group. Additionally, Fluorescence-activated cell sorting (FACS) and immunohistochemistry (IHC) indicated the increases in the CD8+/CD4+ T cell ratio and tumor-infiltrating cytotoxic T cells. In the preventive efficacy study, the saMelan-A/LION substantially delayed tumor progression by inducing an antigen-specific T cell immune response. The results of the ELISpot assay demonstrated that the T cell response specific to Melan-A was significantly increased in the saMelan-A/LION group, different from the result of the immunogenicity study. This indicates that additional exposure to antigens through tumor challenge after vaccination can enhance antigen-specific immune response. Furthermore, the FACS analysis showed an enhanced ratio of effector memory T cells to central memory T cells within the CD8+ and CD4+ cells. These findings suggest that saMelan-A/LION has the potential to be utilized as a therapeutic and preventive vaccine for melanoma.

Despite significant progress in the field of human breast cancer research and treatment, there is a consistent increase in the incidence rate of 0.5 percent annually, posing challenges in the development of effective novel therapeutic strategies. The failure rate of drugs in clinical trials stands at approximately 95

Isoliquiritigenin (ISL), a bioactive phytochemical derived from the root of Glycyrrhiza uralensis, is known to exert anticancer effects by modulating cancer cell functions, including proliferation, metastasis, and autophagy. However, the anticancer effects of ISL on cholangiocarcinoma (CCA) are limited. In this study, we investigated the anticancer effects of ISL on CCA cells (SNU-478 and HuCCT-1). In SNU-478 cells, ISL decreased the expression of glucose-regulated protein 78 (GRP78). ISL was also found to significantly reduce cell viability and colony area of both SNU-478 and HuCCT-1 cells. Furthermore, ISL treatment significantly increased the population of apoptotic cells, as observed through Annexin V/propidium iodide (PI) staining. PI staining showed that the ISL treatment induced significant cell cycle arrest compared to the control group, indicating that ISL-induced decreases in cell viability are associated with cell cycle arrest and apoptosis. ISL treatment also resulted in a significant decline in the mitochondrial membrane potential when observed through JC-10 staining. Mitochondrial superoxide staining revealed that ISL significantly upregulated the generation of mitochondrial reactive oxygen species (ROS). Acridine orange staining indicated that the ISL treatment upregulated lysosomal membrane permeability, which could be related to autophagy. These results suggest that ISL affects the proliferation and apoptosis of CCA cells, which might be related to its regulatory role in various cellular functions, including mitochondrial dysfunction, ROS balance, and autophagy. This study provides empirical evidence that ISL could be a potential candidate for CCA therapy.

Skin aging, accelerated by oxidative stress from environmental factors, results in the breakdown of collagen and elastin, causing visible signs like wrinkles and inflammation. Natural antioxidants such as nicotinamide mononucleotide (NMN), decursin, and l-cysteine have shown potential in combating oxidative damage and inflammation. This study explored the effects of a formulated mixture of these compounds on skin aging and atopic dermatitis (AD) through a combination of in vitro, in vivo, and in silico methods. Using human keratinocyte cells, we assessed cytotoxicity via a cell viability assay, confirming NMN and l-cysteine were nontoxic up to 100 µM, while decursin exhibited toxicity above 10 µM. The intracellular oxidative stress measurement demonstrated that mixtures A and B, composed of the same concentrations of decursin and l-cysteine but differing in NMN levels (low in mixture A and moderate in mixture B), significantly reduced oxidative stress levels induced by 2,2'-azobis(2-amidinopropane) dihydrochloride, whereas mixture C, which contained the highest NMN concentration, was ineffective. Mixture B further reduced senescence-associated heterochromatin foci formation under oxidative stress, while mixture C caused cell structure disruptions. In the dinitrochlorobenzene-induced AD model in BALB/c mice, both, mixture-L and mixture-H treatments reduced epidermal thickness, scratching behavior, and transepidermal water loss, with mixture-L also lowering dermal thickness and mast cell infiltration. Gene expression analysis confirmed that mixture B decreased proinflammatory cytokines like TNF-α and IL-6, while network pharmacology predicted key antioxidant pathways, validated through restored NOS2 gene expression. Overall, the findings highlight the potential of these compound mixtures to mitigate oxidative stress and inflammation, offering a promising approach for skin aging and dermatitis management, though further validation is needed to optimize efficacy and safety.

The search for more effective and safer cancer therapies has led to an increasing interest in combination treatments that use well-established agents. Here we explore the potential of cannabidiol (CBD), a compound derived from cannabis, to enhance the anticancer effects of etoposide in non-small cell lung cancer (NSCLC). Although CBD is primarily used to manage childhood epilepsy, its broader therapeutic applications are being actively investigated, particularly in oncology. Our results revealed that, among various tested chemotherapeutic drugs, etoposide showed the most significant reduction in NSCLC cell viability when combined with CBD. To understand this synergistic effect, we conducted extensive transcriptomic and proteomic profiling, which showed that the combination of CBD and etoposide upregulated genes associated with autophagic cell death while downregulating key oncogenes known to drive tumor progression. This dual effect on cell death and oncogene suppression was mediated by inactivation of the PI3K-AKT-mTOR signaling pathway, a crucial regulator of cell growth and survival, and was found to be dependent on the p53 status. Interestingly, our analysis revealed that this combination therapy did not rely on traditional cannabinoid receptors or transient receptor potential cation channels, indicating that CBD exerts its anticancer effects through novel, noncanonical mechanisms. The findings suggest that the combination of CBD with etoposide could represent a groundbreaking approach to NSCLC treatment, particularly in cases where conventional therapies fail. By inducing autophagic cell death and inhibiting oncogenic pathways, this therapeutic strategy offers a promising new avenue for enhancing treatment efficacy in NSCLC, especially in tumors with p53 function.

The purpose of this study was to evaluate the effects of Sasa borealis 30 % ethanol extract (SBE) on andropause. In TM3 Leydig cells, SBE significantly increased testosterone (T) levels lowered by oxidative stress. SBE also increased the mRNA expressions of 3(3-HSD, 17(3-HSD, and CYP17A1 enzymes, which transform cholesterol into T. Next, for the T-deficient animal models, 23-week-old male Sprague-Dawley (SD) rats were divided into groups of three subjects each: OLD, SB100 (SBE 100 mg/kg BW/day), SB300 (SBE 300 mg/kg BW/day), and YOUNG (7-week-old normal control group). The doses used in this study are within the range of previously reported animal studies using oral administration. The SB300 group showed higher serum T levels compared to the OLD group, while simultaneously enhancing testicular steroidogenesis. The SBE-treated groups showed increased muscle mass, sperm count, and grip strength. Tricin, a phenolic compound in SBE, that significantly increased T production in TM3 cells. We conclude that SBE could improve andropause by increasing the T levels, regulating T synthesis, and alleviating physiological symptoms.

Glioblastoma multiforme (GBM) is the most prevalent high-grade malignant brain tumor and is associated with a very poor prognosis. Currently, there are no targeted therapies available for this cancer, and only general chemical drugs are being used. This is primarily due to the challenges posed by the blood-brain barrier (BBB) in drug delivery and the lack of sufficient research on its pathogenesis. Recently, a strong association between CMV (Cytomegalovirus) and GBM has been reported in various studies, and therapies targeting CMV are now undergoing clinical trials. Especially, dendritic cell (DC) cancer vaccines represent a promising therapeutic strategy for GBM, with CMV pp65 emerging as a particularly relevant target antigen. Recent clinical trials have provided evidence supporting the efficacy of select DC vaccines. Nevertheless, the production of DC vaccines remains a labor-intensive, costly, and time-consuming process, emphasizing the critical need for innovative approaches to overcome these limitations. In this study, we developed IMB-402, containing the Specific T-cell Activating Modulator (STAM) built on our engineered IgM-based multivalent antibody backbone platform, ePENDY (engineered PENtamer boDY). IMB-402 consists of ten CMV pp65-derived peptide-loaded-HLAs linked to ePENDY to stimulate priming signal of CD8+ T cell by TCR cluster. Also, we linked a CD40 agonistic scFv as a costimulatory signal molecule to the J chain of ePENDY, mimicking cognately licensed dendritic cells (DCs) to prevent T cells from entering an anergic state. We observed that IMB-402 can expand CMV pp65-specific CD8+ T cells and functionally activate these cells. Notably, we found that this effect occurs even in conditions where only CD8+ T cells are present, without any DCs. This highlights the potential of IMB-402 as an alternative to DC vaccines, offering a promising treatment option for immunosuppressive cancer patients whose DCs fail to respond appropriately. Moreover, the superior effects on expansion and activation of CMV pp65-specific CD8 T cells, compared to a competing drug currently in clinical trials, suggest that IMB-402 has the potential to become a successful treatment for GBM. Additionally, synergistic effect of IMB-402 with anti-PD1 observed using a humanized mouse model indicates that IMB-402 is expected to have robust anti-tumor activity in combination with immune checkpoint inhibitors. Overall, these findings suggest that IMB-402 could represent a new paradigm in cancer vaccine technology, highlighting its potential for development as a GBM treatment. Sunghyun Yoon, Sungmuk Kang, Yeji Byeon, Dongmin Chun, Hong Kyu Lee, Kyung-gi Hyun, Sunghyun Byun, Eunyoung Cho, Yongjun Kang, Chaerin Yoo, Hong Jai Lee, Chungmin Lee, Kyung-Chul Choi, Gyongsik Ha. Development of multivalent antibody-based novel therapeutic cancer vaccine in glioblastoma multiforme (GBM) treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5826.

Thyroid cancer is a malignant tumor whose incidence is increasing worldwide. While thyroid cancer is treatable and curable, a small number of cases can become metastatic when cancer cells originating in the thyroid gland spread to other parts of the body through the bloodstream or lymphatic system. The most common treatments for thyroid cancer are resection and radioactive iodine therapy. However, these treatments have side effects, such as hypothyroidism and damage to normal non-cancerous cells. Tangeretin is a polymethoxylated flavone found in the peel of citrus plants and has biological activity, including antioxidant, anti-inflammatory, and anti-cancer effects. However, the effects of tangeretin on human thyroid cancer have not been investigated. In this study, the effects of tangeretin on cell proliferation and apoptosis of the thyroid cancer cell line SNU-790 were investigated. To prove the results of this study, A water-soluble tetrazolium salt (WST) assay, cell cycle arrest assay, annexin V/PI, DCF-DA, JC-10, and western blot were used. Treatment with tangeretin decreased SNU-790 cell viability and proliferation ability. Annexin V/PI staining showed that tangeretin increased apoptotic cell death. In the wound healing assay, the tangeretin treatment decreased the wound closure area. In addition, tangeretin treatment increased the level of reactive oxygen species (ROS) in the cytosolic of SNU-790. The JC-10 assay showed that the tangeretin treatment decreased the mitochondrial membrane potential (MMP). Western blot analysis revealed that treatment with tangeretin increased the expression of the tumor protein p53. In conclusion, these results indicated that tangeretin inhibited the progression of thyroid cancer in SNU-790 cells by inhibiting migration ability, inducing mitochondrial dysfunction, and mediating oxidative stress in SNU-790. Hence, this study provides experimental evidence that tangeretin could be a potential candidate for the management of thyroid cancer.