Search Results (767)

Colorectal cancer (CRC) is a major cause of cancer-related mortality among adults younger than 50 years of age, and many tumors show incomplete response or develop resistance to 5-fluorouracil (5-FU)-based chemotherapy. Therefore, new therapeutic approaches that improve CRC sensitivity to existing chemotherapeutic agents are needed. KRAS-associated signaling contributes to CRC growth, metabolic adaptation and treatment resistance. In this study, we investigated whether sulfasalazine (SSZ), a U.S. Food and Drug Administration (FDA)-approved anti-inflammatory drug, could enhance the response of CRC cells to 5-FU and modulate KRAS/mitogen-activated protein kinase (MAPK)-associated signaling. Public dataset analysis using cBioPortal, Kaplan–Meier Plotter and DepMap showed that KRAS is commonly altered in CRC. The analysis also showed that higher KRAS expression was associated with shorter overall survival in 1061 CRC patients, while CRC cell-line models demonstrated KRAS dependency. In 2D cultures, both KRAS-mutant HCT116 and KRAS-wild-type RKO cells showed lower cell viability, reduced colony formation and decreased KRAS expression after SSZ treatment. In 3D cultures, exposure to SSZ reduced early spheroid formation, both as a single treatment and when combined with 5-FU. In established spheroids, SSZ-containing treatments affected cell viability, spheroid growth and morphology, with the most noticeable suppressive effect observed in RKO aggregates. SynergyFinder+ dose-matrix analysis identified dose ranges where SSZ and 5-FU showed additive-to-synergistic effects, leading us to select 600 μM SSZ with 25 μM 5-FU for further validation. Western blot results from PEGDA microwell-derived 3D spheroids showed that SSZ + 5-FU treatment reduced KRAS expression and affected KRAS/MAPK-related signaling. This effect was more pronounced in RKO cells, where downstream pathway suppression was stronger. The combination treatment also increased apoptosis-associated PARP cleavage. At the same time, it reduced Cyclin D1 and GPX4 protein levels and changed the expression of stemness-related markers, including ALDH1A3, CD44, and CD133. Together, these results support SSZ as a candidate repurposed adjuvant that may improve the response to 5-FU in CRC spheroid models and support the use of PEGDA microwell-based 3D platforms for testing combination therapy approaches. Full article

Personalized oncology seeks to selectively block specific dysregulated pathways to arrest cancer development. Increased glutamine metabolism is a hallmark of cancer, and 6-diazo-5-oxo-L-norleucine (DON), a structural analog of L-glutamine, was the first compound used to target the exacerbated nitrogen metabolism observed in cancer cells. However, its clinical application was limited by unacceptable toxicity. With the same goal of blocking glutamine metabolism, several specific glutaminase inhibitors have been characterized in recent decades, showing promising antitumor activity. Nevertheless, this strategy frequently induces adaptive metabolic resistance that must be counteracted. In this context, glutaminase has become a key target in combination therapies for several tumor types aimed at restricting anabolic adaptation when single metabolic therapy fails, emerging as a possible synergistic therapeutic intervention. Consequently, combination therapies that include glutaminase inhibition alongside additional agents to counteract the metabolic plasticity of cancer have emerged as a promising approach in personalized antitumor pharmacology. This review provides a historical-to-translational overview of glutamine-targeted therapies, with particular emphasis on glutaminase inhibitors, including compound 968, BPTES, CB-839, and next-generation inhibitors, as well as DON-derived prodrugs. We discuss their mechanisms of action and their integration with chemotherapy, targeted therapies, radiotherapy, and immunotherapy, highlighting how glutamine metabolism targeting influences tumor metabolic adaptation, redox homeostasis, therapy resistance, and tumor–immune interactions. Finally, we examine current clinical developments, emerging therapeutic combinations, and the challenges that must be addressed for the incorporation of glutamine metabolism targeting into precision oncology. Full article

Triple-negative breast cancer (TNBC) is characterized by a lack of estrogen, progesterone, and HER2 receptors; an aggressive phenotype; high rates of early relapse and metastasis; and the worst mortality rates among all breast cancer subtypes. Currently, there is no effective curative targeted therapy for TNBC and chemotherapy remains the primary treatment for TNBC. Therefore, there is a critical need to develop highly effective, novel therapies to improve patient survival. We previously validated FOXM1, a proto-oncogenic transcription factor, for the first time as a potential molecular target in TNBC through genetic knockdown studies in mice. We show that FOXM1 expression is associated with shorter patient survival and is a marker of poor prognosis. There is no FDA-approved FOXM1 inhibitor. We found that patients with TP53 mutations have dramatically higher FOXM1 expression, indicating that widespread TP53 mutations detected in about 80% of TNBC patients are the major driver of FOXM1 overexpression in TNBC patients. We identified its binding ability using an in silico study, and found it to be a well-known FOXM1 inhibitor that suppresses TNBC cell proliferation, migration, and invasion, and induces apoptosis. In vivo studies in mice bearing TNBC tumors demonstrated that treatment with a novel FOXM1 inhibitor incorporated in single-lipid nanoparticles suppressed the growth of TNBC tumor xenografts. In conclusion, our findings suggest that the novel FOXM1 inhibitor represents a potent and safe therapeutic strategy with significant potential for the treatment of other FOXM1-driven cancers including TNBC that currently have limited treatment options. Full article

Hollow mesoporous silica nanoparticles (HSNs) were synthesized via the Stöber method using resorcinol–formaldehyde resin as a template and further developed as a multifunctional nanocarrier for synergistic chemo–photothermal therapy. Docetaxel (DTX) and indocyanine green (ICG) were co-loaded into HSNs as the prodrug and photothermal agent. The loading sequence of these agents can critically affect encapsulation efficiency. Preloading DTX followed by ICG incorporation achieved the highest drug loading (38.65%) and preserved the photoactivity of ICG. The resulting ICG&DTX@NH₂-HSNs exhibited strong and stable near-infrared photothermal conversion, as well as pH- and laser-responsive drug release behavior. In vitro studies confirmed efficient cellular uptake by 4T1 tumor cells and enhanced cytotoxicity compared with single treatments. In vivo experiments demonstrated significant tumor growth suppression in 4T1 tumor-bearing mice, with the greatest effect observed under combined ICG&DTX@NH₂-HSNs and laser irradiation. Importantly, histological analysis of major organs revealed no obvious toxicity, confirming the biosafety of the present nanoplatform. This study confirmed the potential of hollow mesoporous silica-based nanocarriers as safe and effective platforms for combined chemotherapy and photothermal cancer therapy. Full article

Pancreatic ductal adenocarcinoma is highly malignant with poor prognosis. Its dense tumor microenvironment severely limits the efficacy of conventional chemotherapy and causes severe side-effects. Herein, we adopt the established Schiff-base crosslinked thermoresponsive injectable self-healing poly(2-(2-methoxyethoxy)ethyl methacrylate-co-oligo(ethylene glycol) methyl ether methacrylate-co-aldehyde 2-hydroxyethyl methacrylate)/carboxymethyl chitosan (APMOH/CMCS) hydrogel as the delivery scaffold. By regulating monomer composition, the volume phase transition temperature (T_VPT) of the hydrogel was tuned to around 43 °C to match the therapeutic temperature requirement. Subsequently, copper–metal organic framework (Cu-MOF) nanoparticles co-loaded with 2,2′-azobis(2-methylimidazoline) dihydrochloride (AIPH) and 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) cationic radicals (ABTS·⁺) (denoted as AB@Cu-MOF) were uniformly incorporated into the hydrogel network. Under near-infrared (NIR) irradiation, ABTS·⁺ acts as a photothermal agent to generate hyperthermia for tumor ablation; the elevated temperature further activates AIPH to produce alkyl radicals, which can oxidize inactivated ABTS back to ABTS·⁺ and construct a sustainable photothermal therapy–thermodynamic therapy (PTT-TDT) circulation. Meanwhile, Cu-MOF can consume intracellular glutathione (GSH) to protect active components from deactivation and initiate chemodynamic therapy (CDT) via Fenton-like reactions to produce toxic reactive oxygen species. Benefiting from the thermoresponsive characteristic, the hydrogel undergoes volume shrinkage upon heating, achieving NIR-triggered on-demand drug release with a cumulative release rate of 81.1%. In vitro and in vivo experiments verified that this integrated platform realizes remarkable triple synergistic efficacy of PTT, TDT, and CDT. The tumor volume of the treatment group was merely 13.3% of the control group, and the system also exhibited excellent biocompatibility. Collectively, it offers a feasible and promising intelligent platform for precise local treatment of pancreatic cancer. Full article

The pro-metastatic gene MDA-9/Syntenin-1 and its tandem PDZ domains (PDZ1 and PDZ2) provide established targets for intervening in tumor progression and metastasis. Recently, we generated and validated MDA-9/Syntenin-1 antagonists targeting a single PDZ domain (PDZ1i) or both PDZ domains (IVMT-Rx-3) in carcinomas and melanoma. Data reveal that IVMT-Rx-3 possesses immunomodulatory and anti-angiogenic properties, in addition to its well-established anti-invasive capabilities. Despite its significant druggable properties, it cannot be delivered orally, limiting its clinical potential. Here, we characterized an oral microemulsion (ME) formulation of IVMT-Rx-3, IVMT-Rx-3-ME to enhance intestinal permeability, bioavailability, and therapeutic efficacy. Physicochemical analyses demonstrated that the optimized formulation produced a stable IVMT-Rx-3-ME with high drug content (>90%). In vitro permeability and dissolution assays confirmed improved membrane transport and solubility compared with the free drug dispersion control. Pharmacokinetic studies in rats revealed that the ME enabled rapid absorption and sustained systemic exposure, whereas the free drug showed negligible bioavailability. In murine metastatic melanoma models, oral IVMT-Rx-3-ME suppressed tumor growth and lung metastases, and when combined with anti-PD-L1 antibody, produced synergistic antitumor effects with minimal toxicity. Collectively, these findings highlight IVMT-Rx-3-ME as a potent and viable oral metronomic chemotherapy platform for metastatic melanoma, with enhanced combinatorial translational potential with immunotherapies. Full article

Background/Objectives: Melanoma affects both sexes, and its incidence has increased in recent years. It is currently among the most common types of cancer. Standard chemotherapy, although effective, often lacks selectivity for tumor cells, resulting in dose-limiting side effects. Electrochemotherapy and magnetic hyperthermia have been investigated as innovative biomedical approaches. Electrochemotherapy improves drug delivery by facilitating electroporation, thereby increasing intracellular concentrations of chemotherapeutic agents and reducing associated adverse effects. Furthermore, electroporation enhances sensitivity to magnetic hyperthermia. However, few studies have focused on the combination of electroporation and hyperthermia in melanoma models. This study aimed to evaluate the synergistic effects of intratumoral administration of superparamagnetic iron oxide nanoparticles (SPIONs), electroporation (EP), and magnetic hyperthermia (EHP) on fluorescent melanoma tumors generated with the MV3-GFP cell line. Methods: Fluorescent melanoma tumors were generated using the MV3-GFP cell line. Treatments included SPIONs alone, SPIONs combined with hyperthermia, and SPIONs combined with electroporation and hyperthermia. Tumor size was monitored over 21 and 28 days. Results: SPIONs alone did not affect tumor growth (665 mm³). SPIONs plus hyperthermia reduced tumor size to 126.5 mm³ at day 21. The combination of SPIONs, electroporation, and hyperthermia produced a pronounced antitumoral effect, with tumor size decreasing to 95.5 mm³ at day 14 and 6.8 mm³ at day 21, followed by complete tumor disappearance by day 28. Electroporation significantly enhanced the antitumoral activity of the combined treatment. Conclusions: The combination of SPIONs, electroporation, and magnetic hyperthermia shows significant synergistic antitumoral activity in a melanoma model. These findings support further investigation in larger and more comprehensive in vivo studies to better understand the therapeutic potential of these combined approaches. Full article

The combination of chemotherapy and immunotherapy represents a promising approach that leverages their complementary benefits. However, the side effects resulting from off-target effects and the low efficiency of immune activation remain a significant concern. Herein, we developed a zinc-doped calcium phosphate (ZCP) nanocarrier for the delivery of the chemotherapeutic drug doxorubicin (DOX). By further encapsulating whole proteins from 4T1 breast cancer cells, we constructed a novel nanodrug delivery system named ZCPDM. This system enables specific targeting of tumor cells and undergoes intracellular degradation to release DOX, Zn²⁺, and Ca²⁺. As a chemotherapeutic agent, DOX induces apoptosis while significantly elevating intracellular reactive oxygen species (ROS), thereby enhancing cytotoxicity. This leads to DNA damage and the release of chromosomal fragments. These DNA fragments, together with Zn²⁺, activate the cGAS-STING signaling pathway and trigger pyroptosis, which promotes more efficient recognition and clearance of tumor cells by the immune system. Through these dual mechanisms, ZCPDM effectively combines chemotherapy and immunotherapy. The anti-tumor efficacy and underlying mechanisms were validated at the cellular level. Furthermore, studies in tumor-bearing mice demonstrated its robust anti-tumor performance and ability to suppress tumor recurrence, along with good biosafety. This targeted drug delivery system achieves safe and synergistic chemo-immunotherapy through homologous targeting-mediated pyroptosis and activation of the cGAS-STING pathway, offering a novel and promising strategy for cancer treatment. Full article

Protein arginine methyltransferase 5 (PRMT5) mediates arginine methylation of a wide range of proteins and plays context-dependent oncogenic or tumor-suppressive roles. In cancer, PRMT5 represses several tumor suppressor genes, including E-cadherin, TP53BP1, ST7, PTEN, and RB (retinoblastoma). Elevated PRMT5 expression has been reported across multiple cancer types, notably triple-negative breast cancer (TNBC). In TNBC, high PRMT5 levels are associated with enhanced cancer stem cell self-renewal, increased tumor growth and metastasis, and reduced patient survival. Mechanistically, PRMT5 promotes breast cancer stem cell maintenance and proliferation through stabilization of the transcription factors KLF4 and KLF5. Disruption of the PRMT5–KLF4 axis results in significant tumor reduction in TNBC models. Moreover, increased PRMT5 expression has been linked to resistance to chemotherapy and immunotherapy in TNBC. Notably, PRMT5 inhibitors demonstrate synergistic anticancer activity when combined with inhibitors of key oncogenic signaling pathways, including EGFR, PARP, and AKT. While several PRMT5 inhibitors are currently being evaluated in clinical trials for other malignancies, no clinical trials have yet been initiated specifically for TNBC. Full article

Honokiol (HNK), a bioactive compound found in Magnolia species, is a promising, multifunctional agent with therapeutic effects on breast cancer (BrCa). Preclinical evidence, including in vitro and in vivo studies, suggests that HNK inhibits essential oncogenic pathways and reduces oxidative stress, inflammation, metabolic reprogramming, and cancer stemness. HNK demonstrates synergistic activity with chemotherapy, endocrine therapy, targeted therapy, and immune checkpoint inhibitors, increasing sensitivity to treatment across models of ER+, PR+, and HER2+ BrCas, as well as triple-negative breast cancers (TNBC). Nanotechnological delivery systems enhance the solubility, bioavailability, and intratumoral accumulation of HNK, increasing its translational capacity. Although clinical data remain very limited, current evidence in humans is insufficient to draw definitive conclusions regarding the safety and efficacy of HNK. This review summarizes mechanistic, preclinical, and emerging clinical data, highlights challenges in formulation and pharmacokinetics, and anticipates future trends in incorporating HNK into multimodal therapy for BrCa. Full article

Magnetic fields (MFs) represent an emerging modality in cancer therapy, encompassing static, low-frequency, pulsed, and nanoparticle-mediated alternating fields. These interventions have demonstrated the capacity to modulate proliferation, apoptosis, ferroptosis, migration, and epithelial-to-mesenchymal transition (EMT) in tumor cells, often through reactive oxygen species (ROS) modulation, ion channel regulation, membrane receptor dynamics, and lysosomal membrane permeabilization. Magnetic nanoparticle hyperthermia (MHT) has reached clinical application, showing promising outcomes in glioblastoma and prostate cancer, while pulsed electromagnetic fields (PEMFs) and magneto-mechanical approaches are under preclinical investigation. The mechanistic diversity of MFs allows synergistic combination with chemotherapy, radiotherapy, and immunotherapy. However, parameter sensitivity, field standardization, and long-term safety remain challenges. Here, we review mechanistic insights, signaling pathways, and experimental and clinical evidence for MF-based cancer therapies, highlighting translational potential and the need for rigorous optimization to realize clinical efficacy. Full article

Ferroptosis and cuproptosis are promising anti-tumor treatment strategies. Elesclomol (ES) is a kind of common cuproptosis inducer, and cisplatin (DDP) is a commonly used drug in liver cancer chemotherapy, which can induce cells to undergo ferroptosis. Both of these cell death processes require inducing cells to generate oxidative stress. Therefore, elesclomol and cisplatin may have a synergistic effect in anti-tumor treatment. Here, we designed an active oxygen-responsive nano-delivery system and conducted in vitro and in vivo to study the synergistic anti-liver cancer effect of elesclomol and cisplatin. Our data showed that the elesclomol nanoparticles can effectively inhibit the growth of liver cancer cells and showed extremely low organ toxicity. Elesclomol exhibited a synergistic effect with cisplatin in vitro, but the combined treatment of the two did not outperform single drug treatment in vivo. The reason might be that the nuclear factor erythroid 2-related factor 2 (Nrf2) protein in liver cancer cells is feedback-expressed, inhibiting the oxidative stress effects induced by elesclomol and cisplatin. Therefore, this study provides reference data for exploring the mechanism of elesclomol’s synergistic anti-liver cancer treatment with cisplatin and offers a feasible strategy for future precise liver cancer treatment and improving chemotherapy efficacy. Full article

To address the limitations of the tumor microenvironment (TME) and the inadequate efficacy of standalone chemodynamic therapy (CDT), this study developed a tannic acid-copper coordination gel-coated mesoporous Cu₂O nanodelivery system (Cu₂O@TA@5-FU) for synergistic enhanced CDT and chemotherapy. The system exhibits a high specific surface area (98 m²·g⁻¹) and mesoporosity, achieving a 5-fluorouracil (5-FU) loading efficiency of 46.2%. Under simulated TME conditions, the nanodelivery system displayed markedly accelerated drug release and enhanced catalytic activity, indicative of pronounced TME responsiveness. In vitro, the Cu₂O@TA support efficiently catalyzed a Fenton-like reaction with H₂O₂ to generate cytotoxic hydroxyl radicals (·OH) while depleting overexpressed intracellular GSH, thereby disrupting antioxidant defenses and amplifying oxidative stress. Combined with the antiproliferative action of released 5-FU, the synergistic treatment reduced 4T1 cell viability to approximately 23%, accompanied by sharp declines in intracellular ATP and GSH levels. This work overcomes the systemic toxicity of free 5-FU and the instability of Cu₂O by employing a protective and stimuli-responsive TA-Cu coordination gel shell, offering a reliable strategy for TME-responsive synergistic nanotherapeutics that disrupt tumor metabolic and redox homeostasis. Full article

Hypoxia is one of the most important factors limiting the effectiveness of modern anticancer therapies, particularly photodynamic therapy (PDT). The hypoxia of the tumor microenvironment results from abnormal angiogenesis and the high metabolic demand of cancer cells, which leads to reduced oxygen availability necessary for generating reactive oxygen species (ROS). Consequently, conventional therapeutic approaches, mainly based on the type II PDT mechanism, show limited effectiveness under hypoxic conditions. In response to these limitations, strategies are being developed to increase oxygen availability within the tumor. Of particular importance are nanocarriers based on perfluorocarbons (PFCs), which, due to their high gas solubility, can effectively transport and release oxygen in the tumor microenvironment. Research indicates that the use of such systems leads to improved PDT efficiency by increasing the production of singlet oxygen and enhancing cancer cell damage. Parallelly, alternative approaches independent of high oxygen concentration, including type I photosensitizers, are being developed. Unlike classical type II mechanisms, they generate free radicals through electron transfer reactions, which allows effective action even under conditions of significant hypoxia. This approach significantly expands the possibilities of using PDT in the treatment of tumors with low oxygen levels. Current research directions focus on integrating various therapeutic strategies to achieve a synergistic effect. Hybrid systems combining oxygen delivery (e.g., using PFCs) with the use of type I photosensitizers and other treatment methods, such as chemotherapy or immunotherapy, show the greatest clinical potential. Such multifunctional approaches simultaneously allow improving tumor oxygenation and increasing the efficiency of ROS generation, which makes them a promising strategy for the future of anticancer therapies. Full article

Manganese-based nanomaterials have been novel multifunctional platforms in tumor immunotherapy because of their tunable multivalent states, biocompatibility, and multi-stimulus responsiveness. Current cancer treatments are insufficient and cause severe side effects; therefore, manganese-based nanomaterials are proposed in combination with immunotherapy to mitigate adverse effects. This review outlines the antitumor effects mediated by four key mechanisms: (1) activation of the cGAS-STING immune signaling pathway, (2) direct activation of immune cells, (3) induction of immunogenic cell death (ICD), and (4) modulation of the tumor microenvironment. These approaches are broadly categorized into two types: monotherapy and multimodal combination therapy. Monotherapy encompasses three specific modalities: (1) direct use as a Stimulator of Interferon Genes (STING) agonist, (2) vector-mediated targeted drug delivery, and (3) mediation of chemodynamic therapy to generate reactive oxygen species, thereby inducing ICD. Multimodal combination therapy involves synergistic integration with traditional or emerging treatment modalities, including chemotherapy, radiotherapy, photodynamic therapy, sonodynamic therapy, and low-level light therapy, as well as multimodal combination treatment methods. It significantly enhances the antitumor efficacy of traditional therapies through immunostimulation, thus achieving synergistic breakthroughs in treatment efficiency and survival rate. Collectively, the multifunctional integration of manganese-based materials is a novel strategy for developing “self-adjuvant” immunotherapeutic platforms and investigating the clinical translation potential. Full article