Glioblastoma is a highly invasive primary brain tumor with a poor prognosis, highlighting the need for new therapeutic strategies. Toxins derived from Macrodactyla doreensis have attracted attention for their potential anticancer activity. This study evaluated the anticancer and cytotoxic effects of M. doreensis crude venom on two commonly used glioblastoma cell lines (U251 and LN229), which mirror the phenotype of primary tumors. Cell viability and proliferation were assessed using the CCK-8 assay and colony formation assay, while cell migration and invasion capabilities were detected via wound healing assay and Transwell assay. Annexin V/PI staining and PI-based cell cycle analysis indicated that the crude venom significantly induced cell apoptosis and caused S-phase arrest. Proteomic analysis combined with GO and KEGG enrichment analyses as well as bioinformatics approaches showed that M. doreensis crude venom inhibits glioblastoma cell proliferation by downregulating the expression of CDK2, RRM2, and CHEK1, thereby hindering cell cycle progression and regulating the p53 signaling pathway. Notably, the downregulation of these key glioblastoma-related target genes was validated by qPCR. In addition, network pharmacology analysis indicated that several peptide families present in the sea anemone crude venom, including ShK peptides, inhibitor cystine knot (ICK) peptides, and EGF-like peptides, exhibit notable antitumor potential. Combined with AlphaFold2-based structural modeling and molecular docking, these analyses further elucidated the potential molecular mechanisms underlying their interactions with key targets, such as MD-381 with RRM2, MD-322 with CDK2, and MD-429 with CHEK1. Collectively, these findings highlight the therapeutic potential of M. doreensis crude venom and lay a foundation for the subsequent isolation of novel peptides and their further development in glioblastoma treatment.

Background/Objectives: P-glycoprotein (P-gp, ABCB1/MDR1) is a key ATP-binding cassette transporter involved in multidrug resistance in cancer, limiting intracellular accumulation of various chemotherapeutic (CT) agents. Several antidepressants (ADs) have been shown to modulate P-gp function. This dual pharmacological profile raises the possibility of repurposing ADs as chemosensitizers to enhance anticancer drug efficacy. The objective of this review was to summarize the available evidence on the combined use of ADs and chemotherapeutics to overcome P-gp-mediated resistance. Methods: A systematic search was performed in PubMed, Scopus, and PsycInfo/PsycArticles databases using a comprehensive search string combining terms for P-gp, ADs, chemotherapy, and drug resistance. Inclusion criteria were preclinical or clinical studies investigating the effect of ADs in combination with chemotherapeutics on P-gp-mediated resistance in cancer models. Eleven relevant studies were identified and qualitatively analyzed. Results: Across diverse cancer models, including colon, breast, and multidrug-resistant cell lines, several ADs significantly enhanced the cytotoxicity of many chemotherapeutic agents. The proposed mechanisms involved downregulation of P-gp expression, inhibition of efflux activity, and increased intracellular drug accumulation. Conclusions: The combination of ADs with CT agents shows promising potential in overcoming P-gp-mediated multidrug resistance, enhancing antitumor efficacy in preclinical models. Further translational and clinical research is needed to validate these findings, optimize dosing strategies, and assess the risk-benefit profile in cancer patients, particularly those with comorbid depressive disorders.

ChemoNETosis represents a distinct form of therapy-induced innate immune activation, in which cytotoxic chemotherapy alters the tumor microenvironment (TME) in ways that attract and stimulate neutrophils, ultimately triggering the release of neutrophil extracellular traps (NETs). Unlike classical NETosis, which typically arises in response to infection or sterile inflammation, chemoNETosis is initiated by treatment-related danger signals and chemokine-cytokine loops that reshape the immune landscape and promote the formation of NET-rich metastatic niches. These NET structures serve not only as physical scaffolds but also as bioactive platforms enriched with proteases, reactive oxygen species, and enzymes capable of activating growth factors, collectively driving epithelial-mesenchymal transition, enhanced tumor cell plasticity, immune cell exclusion, changes in vascular permeability, and the development of chemotherapy resistance. While predominantly associated with tumor-promoting effects, chemoNETosis may, under specific genetic or metabolic conditions, contribute to antitumor responses, reflecting its context-dependent plasticity. In this review, we present what is, to our knowledge, the first in-depth synthesis of chemoNETosis across solid tumors, with a focus on key mechanistic nodes and translational perspectives.

Background: First-line chemoimmunotherapy (I + C) is the standard of care for advanced non-squamous non-small cell lung cancer (NSCLC) without oncogenic mutation. Bevacizumab has been shown to enhance the efficacy of chemotherapy in non-squamous NSCLC, yet its added value when combined with I + C (I + C + B) remains unclear. To address this gap, we conducted a real-world comparative study and a network meta-analysis to evaluate I + C + B versus I + C in this setting. Methods: This retrospective study included patients with advanced EGFR/ALK-negative non-squamous NSCLC treated with first-line I + C + B or I + C. Propensity score matching (PSM) was employed to balance baseline characteristics between groups. Efficacy endpoints were progression-free survival (PFS) and overall survival (OS). Subgroup analyses examined outcomes by PD-L1 expression, age, metastases, and chemotherapy, among other factors. In parallel, a network meta-analysis of four randomized trials (n = 2026) indirectly compared I + C + B against I + C for PFS, OS, and safety outcomes. Results: A total of 277 patients were included, with 167 (60.3%) receiving I + C + B and 110 (39.7%) receiving I + C. Before PSM, the I + C + B regimen significantly prolonged PFS versus I + C (hazard ratio [HR] = 0.69, 95% CI 0.52-0.92, p = 0.010), with this benefit maintaining post-matching (HR = 0.70, 95% CI 0.49-0.99, p = 0.045). However, OS did not differ significantly between groups in either the pre-PSM (HR = 0.93, 95% CI: 0.67-1.30; p = 0.665) or matched analyses (HR = 0.84, 95% CI: 0.54-1.29; p = 0.421). Subgroup analyses suggested greater PFS benefit from I + C + B among PD-L1-negative, older patients, those with brain metastases or multiple metastatic sites, and in patients receiving specific chemotherapy doublets. The network meta-analysis confirmed a PFS advantage for I + C + B over I + C (HR = 0.84, 95% CI: 0.71-0.98) without an OS benefit (HR = 0.95, 95% CI: 0.79-1.14). Toxicity was higher with I + C + B; rates of grade 3-5 adverse events, serious adverse events, and treatment discontinuation were all significantly increased compared to I + C. Conclusions: In the first-line treatment of advanced EGFR/ALK-negative non-squamous NSCLC, adding bevacizumab to I + C improved PFS but did not translate into an OS gain. Although PFS benefits were observed in certain subgroups, these were accompanied by significantly increased treatment-related toxicities. Our findings suggest that no clear subgroup has been identified where the benefit outweighs the risks, necessitating extreme clinical caution.

Lenvatinib is an oral multi-kinase inhibitor which is used for the treatment of renal cell carcinoma, non-iodine avid differentiated thyroid cancer, hepatocellular carcinoma, and endometrial cancer. We present a series of three (3) patients who, whilst on treatment with Lenvatinib, developed symptoms and radiological findings of acalculous cholecystitis. A radiological review of another nineteen (19) Lenvatinib-treated patients in our center was undertaken, with another three (3) patients exhibiting radiological features of acalculous cholecystitis with gallbladder wall thickening and pericholecystic fluid collection but without abdominal pain or clinical symptoms of cholecystitis. A literature review is also presented of all previous publications of Lenvatinib-induced acalculous cholecystitis, including the results of two pharmacovigilance studies. This review provides evidence that Lenvatinib-induced acalculous cholecystitis is not as rare as initially thought from the Lenvatinib licensing studies; hence, this is an adverse event that merits more attention. Oncologists using Lenvatinib should be aware of this potential toxicity and be familiar with its management.

Immune checkpoint inhibitors and antibody drug conjugate combinations have revolutionized the management of patients with advanced and metastatic urothelial carcinoma, offering unprecedented survival outcomes. These treatments are now moving into earlier stages of disease, including perioperative treatments for patients with muscle-invasive bladder cancer planning for curative-intent radical cystectomy. In this setting, there are now standard-of-care options for adjuvant immune checkpoint inhibitors with or without prior neoadjuvant chemotherapy, perioperative immune checkpoint plus cytotoxic chemotherapy combinations, and perioperative immune checkpoint inhibitor plus antibody drug conjugate combinations. This review will evaluate key clinical trials that led to modern standards of care involving these classes of drugs and highlight ongoing clinical trials that may further shift treatment paradigms for muscle-invasive bladder cancer. Key efficacy and toxicity considerations will be reviewed, and available evidence for biomarkers will be evaluated. As immune checkpoint inhibitors and antibody drug conjugates continue to demonstrate improved outcomes across the spectrum of bladder cancer treatment, understanding their role in the muscle-invasive disease state is crucial to managing patients with this condition.

Drug therapy serves a key role in the treatment of cervical cancer, which is one of the most common types of solid tumor in female patients. Therefore, it is important to seek more effective and less toxic therapies. Protein arginine methyltransferase 5 (PRMT5) is a key oncogenic target in cervical cancer, providing a rational basis for the development of targeted therapeutic agents. MS4322 is a highly selective proteolysis targeting chimera degrader specifically targeting PRMT5. Therefore, the present study aimed to investigate the therapeutic potential of MS4322 against cervical cancer and the underlying molecular mechanisms. The effects of MS4322 on human cervical HeLa cells were investigated by Cell Counting Kit‑8, clone formation, wound healing and Transwell assay, flow cytometry, immunofluorescence staining, immunohistochemistry and small interfering RNA assay. PRMT5 expression was upregulated in cervical cancer tissue, and functional analyses confirmed that PRMT5 promoted the proliferation of cervical cancer cells. MS4322 significantly decreased PRMT5 mRNA expression, as well as the proliferation, migration, invasion and clone formation ability of HeLa cells, leading to cell cycle arrest in G0/G1 phase and inducing apoptosis. Mechanistically, MS4322 downregulated the expression of PRMT5, β‑catenin, Wnt‑3a, and c‑myc, while upregulating GSK‑3β, thereby inactivating the Wnt/β‑catenin pathway. These findings indicated that MS4322 exerted anti‑tumor effects via regulating the PRMT5/Wnt/β‑catenin pathway and may serve as a promising candidate agent for cervical cancer treatment.

Immune checkpoints are one of the mechanisms that maintain the balance between immunotolerance and immunopathology. These mechanisms are often exploited by tumour cells. Thanks to extensive global testing of anticancer drugs, a revolutionary cancer therapy based on immune checkpoint inhibitors (ICIs) has been developed. Some pathogens exploit regulatory checkpoint interactions, contributing to the establishment of hidden, long-term, or persistent infections in which the host is unable to eliminate the pathogen. However, a structured overview of immune checkpoint involvement in bacterial infections remains underrepresented in the current scientific literature. We conducted a literature review focusing on the documented role of selected immune checkpoints (specifically PD-1, PD-L1, TIM-3, LAG-3, CTLA-4, and TIGIT) during infections of humans and animals with clinically relevant bacterial pathogens from the Actinobacteria, Chlamydiae, Firmicutes, Proteobacteria, and Spirochaetae phyla. The current state of knowledge suggests that applied research into immune checkpoints and the controlled use of ICIs has great potential to improve the diagnosis, treatment, and prognosis of serious human bacterial infections.

Byakangelicol (BYA) belongs to coumarins, which have anti-inflammatory and anti-tumor pharmacological properties, but its inhibitory effect on liver cancer and its mechanism are still indistinct. This study explored the mechanism of action by which BYA affects hepatocellular carcinoma (HCC). Cell cytotoxic and apoptosis assay results showed that BYA effectively killed three kinds of HCC cells and induced mitochondrial pathway apoptosis of HepG2 cells. Furthermore, the results of network pharmacological analysis, flow cytometry and western blot assays demonstrated that BYA can induced reactive oxygen species (ROS) accumulation, which in turn upregulated the phosphorylation expression of JNK and p38 while downregulating the phosphorylation expression of AKT, ERK, and STAT3. Meanwhile, the expression of these proteins was reversed after MAPK inhibitors pretreatment. Cell cycle and cell metastasis assay results showed that BYA can induce G2/M phase arrest and inhibit cell metastasis. At the same time, the expression of related proteins was reversed after ROS inhibitors (N-Acetyl-l-cysteine) pretreatment. The research results reveal that BYA can cause the accumulation of ROS within cells, and induce apoptosis in HepG2 cells through the mitochondrial pathway, thereby leading to cell cycle arrest at the G2/M phase and inhibition of cell migration ability. This study provides theoretical support for the clinical application of BYA in the treatment of HCC.

Immune checkpoint inhibitors (ICIs) have emerged as a promising treatment for various cancers, including advanced hepatocellular carcinoma (HCC). However, a significant proportion of patients with HCC, particularly those with metabolic dysfunction-associated liver disease (MASLD), exhibit resistance to ICI therapy. Studies have revealed that the presence of specific gut bacteria, such as Akkermansia, Bifidobacterium, and Lachnoclostridium, is associated with improved outcomes with ICI-treated HCC patients. Conversely, the overgrowth of bacteria like Enterobacteriaceae is linked to resistance to therapy. This review investigates the role of gut microbiota in shaping immune checkpoint inhibitor responses in MASLD-related hepatocellular carcinoma, focusing on how dysbiosis may contribute to ICI resistance and exploring microbiome modulation strategies, such as fecal microbiota transplantation and probiotics, aiming to optimize therapeutic outcomes.

Multidrug resistance (MDR) remains a major challenge in small cell lung cancer (SCLC), limiting the efficacy of chemotherapeutics like doxorubicin. This study investigates whether silencing cellular prion protein (PrP), a known MDR-associated molecule, can enhance doxorubicin-induced cell death in Adriamycin-resistant H69AR cells. Quantitative RT-PCR and immunocytochemistry were used to assess the expression of PRNP, CD44, BAX, and BECN1 under various treatment conditions, including doxorubicin exposure and PrP knockdown via siRNA. Autophagic activity was evaluated using monodansylcadaverine (MDC) staining. PrP knockdown significantly reduced PRNP expression and modulated CD44 mRNA levels, especially during doxorubicin co-treatment. However, CD44 protein levels remained unchanged, suggesting post-transcriptional regulation. BAX expression increased with doxorubicin and siRNA individually, but not in combination, indicating a PrP-independent mechanism. BECN1 expression and Beclin-1 protein levels were significantly elevated in all treatment groups, especially in siRNA/doxorubicin combination. MDC staining confirmed increased autophagic vacuole formation in this group, indicating activation of Beclin-1-mediated autophagy. In conclusion, PrP knockdown may sensitize resistant SCLC cells to doxorubicin and promote autophagy. These findings support PrP silencing as a promising strategy to reverse chemoresistance in SCLC.

Cancer therapy-related cardiac dysfunction (CTRCD) is a well established and potentially life-threatening complication of contemporary oncologic treatment. Although comprehensive cardio-oncology guidelines have been developed, their integration into routine hematology and oncology practice remains inconsistent. This consensus statement, developed by a multidisciplinary panel of cardio-oncology experts, aims to provide practical, case-based guidance to help oncology providers recognize, assess, and manage CTRCD across a spectrum of malignancies and cardiovascular presentations.

To evaluate the efficacy and safety of sequential immune checkpoint inhibitors (ICIs) following concurrent chemoradiotherapy (CCRT) in older (≥70 years) patients with locally advanced esophageal squamous cell carcinoma (ESCC).

Radiation therapy (RT) offers a tool to enhance immune checkpoint inhibitor (ICI) efficacy, yet its immunomodulatory potential remains poorly understood. Here, we investigated how RT dose-fractionation regimens shape local and systemic antitumor immunity.

Current cervical cancer treatments have yet to realize significant advances in patient quality of life. To overcome the challenges of off-target toxicity and inefficient delivery, we developed targeted ROS-responsive selenium nanoparticles, based on selenium's anticancer properties.

The 1,2,4-oxadiazole scaffold has attracted considerable interest as a privileged structure for anticancer drug development due to its favorable physicochemical properties and multimodal bioactivity. This study presents a comprehensive computational investigation to evaluate the potential of a series of 1,2,4-oxadiazole derivatives as dual inhibitors of the human epidermal growth factor receptor 2 (HER2) and estrogen receptor alpha (ERα), two key drivers in these malignancies. An integrated in silico strategy was employed, combining density functional theory (DFT), molecular docking and dynamics simulations, pharmacokinetic profiling, and machine learning models. Our workflow identified several lead compounds exhibiting promising dual-binding characteristics. Key derivatives demonstrated superior predicted binding affinity and complex stability compared to the reference inhibitor erlotinib. Pharmacokinetic evaluations indicated that the series possesses favorable drug-likeness, with high predicted oral bioavailability and a low risk of cardiotoxicity. Furthermore, machine and deep learning models achieved robust performance in classifying compound activity, underscoring their utility in virtual screening. Collectively, this work validates the 1,2,4-oxadiazole core as a promising scaffold for dual HER2/ERα inhibition and provides a rational, multi-faceted computational blueprint. The identified lead compounds warrant subsequent experimental validation, and the established framework serves as a valuable template for accelerating the discovery of next-generation targeted cancer therapies.

Bullous pemphigoid (BP) induced by immune checkpoint inhibitors (ICI-BP) is a rare immune-related adverse event that affects patient prognosis and management; however, comparative data between ICI-BP and non-ICI BP, especially the dynamic changes of antibodies remain scarce. Therefore, we conducted this study to compare clinical presentation, immunological profile, treatment, management, and outcomes of ICI-BP versus non-ICI BP. This was a retrospective, single-centre cohort study of consecutive patients between 2019 and 2025. Patients with ICI-BP (Group A) were compared with Group B (BP with concurrent malignancy but no ICI exposure) and Group C (classic BP). There were 34, 10, and 68 patients enrolled in Groups A, B, and C, respectively (median follow-up 24.5 months, IQR 10.8-50.0). ICI-BP presented at a younger age (median, 59.0 years; IQR, 53.3-69.5; p < 0.001) and showed a marked male predominance (88.2%; p = 0.003). A transient, albeit non-significant, rise in anti-BP180 reactivity was observed during the first 2 months in ICI-BP. Systemic glucocorticoids were required more frequently in ICI-BP, and IL-4 inhibitors demonstrated superior potency in accelerating BP180 antibody decline compared to non-systematic therapy. Tumour response rates were similar between Groups A and B, as was mortality across the three groups. In conclusion, ICI-BP differs from non-ICI BP in clinical and immunological features and more often necessitates systemic glucocorticoid therapy, while IL-4 inhibitors potentially expedite the reduction of anti-BP180 antibodies in ICI-BP patients.

Cancer progression is driven by dysregulation of cyclin-dependent kinase 2 (CDK2), a critical cell cycle regulator. This study employed an integrated computational approach combining Density Functional Theory (DFT), molecular docking, molecular dynamics (MD) simulations, and MM-PBSA calculations to evaluate 2-thiohydantoin derivatives as CDK2 inhibitors. DFT calculations revealed compounds 2b-e narrowest lowest unoccupied molecular orbital (LUMO)- highest occupied molecular orbital (HOMO) gaps (3.02-3.26 eV in DMSO) and highest electrophilicity indices (> 3.20 eV), indicating enhanced reactivity toward biological targets. QTAIM and Fukui function analyses identified key electrophilic centers (C2, O12, C14) and hydrogen bonding sites essential for protein interactions. Molecular docking against CDK2 (PDB: 1HCK) showed compounds 2c, 2d, and 2b exhibited superior binding affinities (-9.312, -9.303, and - 9.269 kcal/mol) compared to ATP (-8.460 kcal/mol), forming critical hydrogen bonds with Lys33 and Thr14. The 10 ns MD simulations confirmed stable binding, with compound 2f maintaining highest conformational stability (RMSD ~ 0.05 nm) and robust hydrogen bonding (mean: 2.70 bonds). MM-PBSA analysis revealed compound 2d achieved optimal binding affinity (ΔG_bind = -34.50 ± 0.42 kcal/mol) through balanced van der Waals interactions (-50.74 kcal/mol) and minimal desolvation penalty (52.40 kcal/mol). Compounds 2b, 2c, 2d, and 2f emerged as lead candidates for experimental validation as next-generation CDK2-targeted anticancer agents.

Anti-glomerular basement membrane (anti-GBM) disease is a rare, life-threatening small vessel vasculitis affecting the kidneys and lungs, caused by autoantibodies against type IV collagen. Immune checkpoint inhibitors (ICIs) are an oncology treatment that block suppressive molecules on antitumour T lymphocytes, encouraging the immune system to attack cancerous cells. We report the case of a man in his 60s receiving the ICI pembrolizumab for lung adenocarcinoma, who presented with acute renal failure requiring renal replacement therapy and was diagnosed with anti-GBM disease. This case highlights potentially important mechanistic links between lung cancer, immunotherapy and anti-GBM disease development. In line with previous research, there is evidence that breakdown of self-tolerance in response to ICIs may predispose patients to the development of autoimmune disease. In patients on ICIs presenting with acute renal failure, it is important to consider anti-GBM disease as an aetiology alongside more common acute tubulointerstitial nephritis seen in immune-related adverse events of the kidney.

Anticancer peptides (ACPs) are short bioactive sequences that selectively target tumor cells with minimal toxicity, positioning them as promising candidates for next-generation cancer therapies. However, existing computational models face limitations in sequence representation and class imbalance. To address these challenges, we propose UACD-ACPs, a unified fusion-driven framework that integrates a diffusion-inspired noise-conditioned classifier for ACP prediction and a diffusion-based peptide generation module with cancer-type-aware organization for targeted downstream screening. The classification module integrates ProtBERT-based semantic embeddings with physicochemical descriptors via the Multiscale Embedding Compression Strategy (MECS) and a diffusion-inspired noise-conditioned encoder, substantially enhancing predictive robustness and accuracy, particularly under challenging imbalanced multi-class settings. In the generative pipeline, we introduce a denoising diffusion-based generative framework augmented by two novel fusion modules: the Bitemporal Fusion Module (BFM) and the Temporal Feature Attention Module (TFAM). These modules perform multi-scale temporal and semantic fusion to promote the generation of structurally coherent and functionally relevant peptide candidates. Experimental results demonstrate that UACD-ACPs outperforms state-of-the-art methods in terms of accuracy, F1-score, and AUC-ROC. The generated peptides exhibit favorable physicochemical properties, diverse secondary structures, and strong structural stability, as validated by molecular dynamics simulations and membrane-binding analyses. Overall, this study highlights the potential of fusion-driven diffusion-based frameworks for alleviating class imbalance and data heterogeneity in anticancer peptide modeling, paving the way for scalable and biologically grounded ACP discovery.