Cucurbitacin B in cancer: A comprehensive review of its targets and molecular mechanisms.

Transition metal-mediated bioorthogonal reactions face significant challenges, including limited catalytic stability in biological media, sensitivity to environmental conditions, high toxicity, and unpredictable reactions with the prodrugs. Herein, we present a self-reporting biopalladium pre-catalyst, which simultaneously generates catalytic activity through an in situ ligand exchange process in tumor tissue and a turn-on near-infrared fluorescence signal to indicate the optimal reaction time point with the prodrug. Ultrathin 2D metal-organic nanosheet (Pd-BDP) is crafted as a bioorthogonal pre-catalyst with good biocompatibility, which servesd as a reservoir of Pd(II) and avoids its rapid deactivation in living systems. Pd-BDP is activated by electron-poor tri(2-furyl) phosphine (TFP) to generate a Pd complex with a decaging yield of 63.3% under complex physiological conditions, and the process could be simultaneously visualized by NIR fluorescence signals from released BDP photosensitizer. Combination treatment of the immunotherapeutic agonist prodrug (R848) and PDT/PTT-induced ICD facilitates strong antitumor immunity and reduces systemic inflammation, leading to precise inhibition of primary tumor growth and lung metastasis in the mouse model. This study thus opens a new avenue for rational design of bioorthogonal pre-catalysts with a good balance between biocompatibility, stability, and catalytic activity, which underlines its potential to improve the safety and efficacy of synergistically bioorthogonal immunotherapy.

Cell-based therapies using macrophages for tumor-targeted drug delivery show great promise, but are hindered by limited drug loading, complex fabrication, and premature payload release. Current hitchhiking strategies often suffer from low cargo retention, nanoparticle endocytosis, and detachment. A universal, simplified system balancing high loading, controlled release, and cellular localization is urgently needed. Here, we report a macrophage-anchored gated nanofibers platform (MAGF) that addresses these challenges via polyphenol-gated electrospun nanofibers. Doxorubicin-loaded PLGA nanofibers are fabricated via electrospinning and coated with a Fe3⁺-tannic acid (TA) supramolecular network, forming a pH-responsive polyphenol gate. This design enables ultra-high drug loading (∼25wt.%) and minimizes premature leakage under physiological conditions. Importantly, the nanofibers stably adhere to the macrophage surface without internalization, preserving cellular viability, motility, and tumor-homing capacity. Molecular dynamics and density functional theory simulations reveal that strong TA-drug interactions suppress release at neutral pH but dissociate in acidic tumor environments, ensuring site-specific activation. In vivo, MAGF-loaded macrophages demonstrate enhanced drug accumulation in melanoma tumors, significant inhibition of both primary growth and lung metastasis, and favorable biosafety. This work introduces a robust and cell-compatible delivery platform that bridges synthetic nanotechnology with living-cell therapy, offering a generalizable strategy for next-generation, tumor-targeted chemotherapy.

BackgroundDendritic cells (DCs) play a predominant role in antitumor immunity. As professional antigen-presenting cells (APCs), DCs can be functionally matured by TLR2 ligand binding to enhance innate immune response and subsequent T cell-dependent adaptive immunity. DC function is often suppressed by the tumor microenvironment, while current TLR2 agonists exhibit suboptimal stability and diminished efficacy in vivo. Therefore, reactivation of suppressed DCs could be a promising strategy for enhancing the efficacy of cancer immunotherapy.MethodsTo investigate the antitumor immunity induced by the novel Toll-like receptor 2 (TLR2) agonist SUP3 with better stability, we established murine melanoma, colon cancer and breast cancer tumor models. The hematopoietic growth factor Flt3L-dependent dendritic cells (FLDCs) were generated and utilized to examine their capacities of antigen processing and cross-presentation, and migration to the tumor-draining lymph nodes (TdLNs) in response to SUP3 treatment. To further improve the antitumor response of SUP3 by increasing the abundance and activation of DCs, Flt3L was administrated in vivo in combination with immune checkpoint blockade.ResultsSUP3 exhibited stronger inhibition of tumor growth and metastasis than classical TLR2 agonist, Pam3. SUP3 could increase cDC1 antigen cross-presentation and TdLN migration, promoting the proliferation, activation and cytotoxicity of antigen-specific cytotoxic T lymphocytes (CTL). SUP3 promoted the intracellular accumulation of antigens and facilitated the process of antigen cross-presentation, the processe regulated by the small GTPase Rab7. SUP3 induced PD-L1 expression by DCs via an interferon-γ-independent pathway. The combination of SUP3 treatment with immune checkpoint blockade by anti-PD-L1 further improved the antitumor response. Moreover, Flt3L increased DC proliferation and infiltration into the tumor tissues that further enhanced the effects of antitumor immunotherapy when used in combination with SUP3 and anti-PD-L1.ConclusionsThis study demonstrated that the modified and more stable TLR2 agonist SUP3 provided an optimal strategy for promoting antitumor immunity via activation of cDC1. SUP3 enhanced antigen cross-presentation by cDC1 and subsequent activation of CTLs. The antitumor effect was further enhanced when SUP3 and Flt3L synergized with PD-L1 blockade. Therefore, reactivation of suppressed DCs in tumor microenvironment would be a promising strategy for designing effective antitumor immunotherapy.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13046-025-03571-9.

Propolis is a well-known sticky, resinous substance collected by honeybees (Apis mellifera) from the buds of trees and other plants, then mixed with beeswax and their own glandular secretions. Its chemical composition varies widely depending on the bee species, geographic location, plant sources, and weather conditions. The therapeutic potential of propolis-including antimicrobial, anti-inflammatory, and anticancer effects-has been recognized since antiquity. Cancer remains one of the leading causes of morbidity and mortality worldwide. High levels of hypoxia within tumor tissue significantly contribute to cancer progression and increase the resistance of tumor cells to radio- and chemotherapy. In the tumor microenvironment, cytokines play key roles in processes such as invasion, metastasis, and immune suppression. The concept of the "cytokine field" describes how elevated cytokine levels within the tumor microenvironment create a field effect, influencing surrounding cells. Current research is exploring the use of natural immunomodulators, such as propolis, in combination with conventional chemotherapeutic agents for cancer treatment. This review summarizes the potential immunomodulatory role of propolis within the tumor microenvironment.

Gastric cancer (GC) remains a significant global health challenge, often diagnosed at advanced stages due to the absence of reliable early detection biomarkers. In this study, we collected serum samples from multicenter, demonstrating elevated serum levels of LINC 02086 exhibit high diagnostic accuracy. LINC 02086 significantly upregulated in GC tissues, with its expression correlating with poor patient survival. As a driving factor of GC, Helicobacter pylori infection upregulates LINC 02086. Mechanistically, we found METTL3-mediated N6-methyladenosine modification of LINC 02086 promotes GC progression, which upregulates HuR by sponging miRNA-139. We also explored the therapeutic potential of LINC 02086-targeted siRNA delivered via lipid nanoparticles, showing significant inhibition of GC growth and metastasis. These findings position LINC 02086 as a promising serum biomarker for early GC detection and as a potential therapeutic target, paving the way for improved diagnostic and treatment strategies in GC.

Colon cancer metastasis-associated protein 1 (MACC1) was initially identified in colorectal cancer and is linked to metastasis and prognosis in various malignant neoplasms. Anterior gradient homology protein 2 (AGR2) has emerged as a significant prognostic indicator for multiple cancers, while anti-cancer 1 (KAI1), recognized as a tumor metastasis suppressor gene, plays a critical role in cancer progression. Despite their individual associations with metastasis and prognosis across different cancer types, the interactions among MACC1, AGR2, and KAI1 specifically in cervical squamous cell carcinoma remain poorly understood. Therefore, this study aimed to investigate the relationships between MACC1, AGR2, and KAI1 within the context of cervical squamous cell carcinoma, while also examining their correlations with clinicopathological features and overall survival (OS) outcomes in affected patients. Immunohistochemistry was used to detect the expression of MACC1, AGR2, and KAI1 in 106 cases of cervical squamous cell carcinoma. At the same time, the clinicopathological parameters and postoperative survival information were collected. In cervical squamous cell carcinoma, the detection rates of MACC1 and AGR2 were found to be significantly elevated, whereas the detection rate of KAI1 was notably reduced when compared to control tissues. Furthermore, the positive detection rates of MACC1 and AGR2 exhibited a positive correlation with tumor grade, tumor-node metastasis classification, and lymph node metastasis (LNM) stage, while demonstrating a negative correlation with OS. Conversely, the positive detection rate of KAI1 was negatively associated with tumor grade, tumor-node metastasis classification, and LNM stage. Patients within the KAI1 positive subgroup experienced a significantly extended OS in comparison to those in the KAI1 negative subgroup. Additionally, multivariate analysis indicated that the positive expression of MACC1, AGR2, and KAI1, alongside tumor stage and LNM stage, could serve as independent prognostic indicators for OS in individuals diagnosed with cervical squamous cell carcinoma. MACC1, AGR2, and KAI1 may represent potential metastatic and prognostic biomarkers, as well as promising therapeutic targets for squamous cell carcinoma of the cervix.

Chemoresistance remains a crucial obstacle in breast cancer therapy. The mechanisms underlying chemoresistance need to be explored urgently and in depth. Breast cancer metastasis suppressor 1 like (BRMS1L), a core component of the Sin3A–histone deacetylase (HDAC) co-repressor complex, has been reported to suppress breast cancer metastasis through epigenetically regulating the Wnt signal pathway. However, whether BRMS1L could regulate chemosensitivity has not been explored. Herein, we found that higher BRMS1L expression was significantly correlated with increased chemotherapy sensitivity and better prognosis in patients receiving neoadjuvant chemotherapy. In vitro experiments confirmed that chemoresistant breast cancer cells exhibited decreased BRMS1L expression compared to chemosensitive cells. In vivo experiments in nude mice demonstrated that BRMS1L markedly strengthened the chemotherapy effects on xenografts. RNA sequencing (RNA-seq) was performed to elucidate the molecular mechanism underlying BRMS1L-mediated chemosensitivity. Bioinformatics analysis indicated that BRMS1L promotes chemotherapy sensitivity by regulating cellular autophagy. Furthermore, chemoresistant breast cancer cells exhibited elevated autophagy levels, and ectopic expression of BRMS1L significantly suppressed protective autophagy through downregulating ATG5. Collectively, these results revealed that BRMS1L enhances chemotherapy sensitivity via inhibiting protective autophagy. To our knowledge, this is the first study that showed that reduced BRMS1L expression is associated with poor response to neoadjuvant chemotherapy and unfavorable prognosis in breast cancer patients. Our findings reveal a novel role of BRMS1L in chemosensitivity and highlight its potential clinical application in the treatment of breast cancer.

Spirulina platensis (S. platensis) is a natural microalgae extract that exerts significant cytotoxic effects against different serious cancerous diseases. Lung cancer is one of the most common and leading causes of death all over the world. The purpose is to investigate the anti-proliferative cytotoxic effects of S. Platensis against the adenocarcinomic human alveolar basal epithelial cells (A549 cell line). Also, molecular docking Analysis and pathway Map were investigated. The viability of the cells was determined via the MTT assay. Moreover the lipid peroxidation, total thiol, the protein concentration of Microtubule-associated tumor suppressor 1 (MTUS1), P16, Kirsten rat sarcoma viral oncogene homolog (K-ras), the epidermal growth factor receptor (EGFr), and the molecular parameters (short stature homeobox 2 (SHOX2), Breast cancer metastasis suppressor 1 (BRMS1), B-cell lymphoma 2 (BCL-2), and Bcl-2-associated X protein (BAX) were assessed. In order to define interaction sites and classes, the current study investigates in detail the interactions between the ligand S. platensis and the Interleukin enhancer-binding factor 3 Receptor (IL-F3) of lung cancer. Covalent bonds, H-bonds, and hydrophobic interactions were observed to form with critical residues on the active site. Covalent bonds are identified in seventeen of the complexes. A correlation was observed between binding affinity and molecular size, branching, polar surface area of up to 199 Å2, hydrophilicity, and topological diameter for various bonds. In an effort to enhance pharmaceutical quality control, we utilized in silico methodologies to forecast the ADMET (absorption, distribution, metabolism, excretion, and toxicity) of S. platensis. Results revealed a great anti-proliferative cytotoxic effect with a concentration gradient through decreasing the peroxidation content, and the epigenetic markers, with significant up-regulations of the BRMS1 and BAX. In addition to the kinetic and MAP pathways, docking analysis confirmed that S. platensis binds with the highest affinity to the predicted active sites of the tumor receptor IL-F3, thereby validating its antitumor activity. In conclusion, great suppression in the virulence of lung cancer was reported following treatment with S. platensis, illustrating its suspected mechanism of action, safety profile, kinetic properties, molecular docking results, toxicity, and internal pathways.

Mitochondria-targeted carbon monoxide delivery nanoplatform for enhanced cancer immunotherapy through metabolic-immune reprogramming.

Identification of novel targets is critical for the effective management of HCC. UFMylation, a novel ubiquitin-like modification, plays an important role in various biological processes and disease progression. We found that WW domain binding protein 11 (WBP11) is enriched and predicts poor prognosis in HCC. Depletion of WBP11 inhibits the malignancy of HCC cells in vitro and in vivo. Mechanistically, the N-terminal of WBP11 interacts with the RNA recognition motif (RRM) domain of Non-POU-domain-containing octamer-binding protein (NONO) and enhances glycolysis in HCC cells. WBP11 maintains protein stability of NONO by competitively inhibiting UFM1-specific ligase 1 (UFL1)-induced UFMylation of NONO at Lys198. Enforced-NONO expression restores the suppression of growth and metastasis caused by WBP11 depletion or UFL1 overexpression. Overall, our study identifies a key role of the WBP11-NONO axis in HCC progression and reveals the importance of UFMylation in cancer, highlighting potential anticancer strategies by targeting the WBP11-regulated new types of posttranslational modifications.

"Three-birds with one stone" self-assembled carrier-free drug delivery system for efficient inhibition of breast cancer growth and metastasis.

C/EBPβ stabilizes oxidative stress in triple-negative breast cancer cells, driving taxane resistance and immune evasion.

Current status and future perspectives of drug delivery systems loaded with baicalein and baicalin in cancer therapy.

Anticancer effects and mechanisms of genus Dioscorea: A review.

RKIP and tumor immune evasion: Remodeling the immunosuppressive tumor microenvironment.

Thiosemicarbazones down-regulate N-Myc expression in neuroblastoma cells via transcriptional and post-translational mechanisms.

Discovery of the erianin derivatives as EGFR/tubulin dual-target inhibitors that suppress the proliferation and invasion of non-small cell lung cancer through autophagy-dependent ferroptosis.

Disruptions in lipid metabolism can hasten disease progression and impose a heavier burden on patients with nasopharyngeal carcinoma (NPC). We previously observed a positive correlation between zinc finger and BTB domain-containing protein 7A (ZBTB7A) and the long non-coding RNA antisense non-coding RNA in the INK4 locus (ANRIL), indicating a potential link between NPC and lipid metabolism; however, the underlying mechanism remains unclear. This study investigated primary NPC tissues that had significantly lower ZBTB7A expression than that in normal nasopharyngeal epithelium. Subsequent results confirmed that ANRIL promoted ZBTB7A expression by sponging miR-339-5p. ZBTB7A directly promoted ANRIL expression but inhibited SREBP1 and FASN expression. Thus, the ANRIL/miR-339-5p/ZBTB7A axis creates a positive feedback loop that suppresses the lipid pathway. Combining stable ANRIL overexpression with ZBTB7A shRNA effectively reduced lipid metabolism and the migratory, invasive, and metastatic capacities of NPC cells invitro and invivo. Furthermore, the SREBP inhibitor, fatostatin, enhanced the suppression of NPC metastasis. Our results indicated that interventions targeting ANRIL-shZBTB7A and SREBP inhibitors can effectively disrupt lipid metabolism and impair the invasive and metastatic properties of NPC cells. These findings provide valuable insights into the potential experimental strategies for inhibiting NPC metastasis.

Rationale:Extracranial metastases of primary brain tumors are rare, and there is no effective treatment. Here, we report a patient with anaplastic oligodendroglioma (AO, WHO grade III) who effectively delayed survival time after receiving temozolomide (TMZ), immunotherapy, and radiotherapy.Patient concerns:A 42-year-old man underwent surgery and chemoradiotherapy for AO, 41 months ago.Diagnosis:The patient developed lower back pain, and Positron emission tomography/computed tomography (PET/CT) did not detect any lesions other than the skeleton. Sacral aspirate smear showed atypic cell nests, and immunohistochemistry and fluorescence in situ hybridization testing supported the diagnosis of WHO grade III AO and IDH mutations.Interventions:The patient was treated with TMZ, immunotherapy, and local palliative radiotherapy and was stable for 6 months, but the medication was discontinued due to severe myelosuppression.Outcomes:After drug withdrawal, the disease progressed further, with intracranial recurrence and metastasis to the liver, supraclavicular and axillary lymph nodes. The time from the diagnosis of extracranial metastasis to death was 10 months.Lessons:This case show that immunotherapy, oral low-dose TMZ and local palliative radiotherapy may be effective ways to prolong the survival of patients with extracranial metastasis and severe bone marrow suppression.