Glioblastoma (GBM) remains a lethal primary brain tumor, in part because therapeutic efficacy is limited by the blood-brain barrier (BBB) and the complex tumor microenvironment (TME). Sonodynamic therapy (SDT), i.e., use of ultrasound to activate chemical sensitizers and generate cytotoxic stress, offers a non-invasive strategy for treating deep-seated intracranial disease, but progress is constrained by the scarcity of validated sonosensitizers and the inefficiency of conventional in vitro screening methods. Here, we introduce a New Approach Methodology (NAM) that couples a neural network-based positive-unlabeled (PU) learning framework with a high-throughput, magnetic field-guided 3D bioprinting platform to accelerate identification and experimental validation of SDT-sensitizing agents. Using curated drug and small-molecule data and RDKit-derived molecular descriptors, the PU classifier identifies candidate ultrasound-responsive compounds without requiring reliable negative labels. We then validate the AI-based predictions in physiologically relevant U-87 MG glioblastoma spheroids that reproduce key TME features, including spatial heterogeneity and a hypoxic core. The NAM identifies two FDA-approved drugs, carboplatin (advanced ovarian cancer) and memantine hydrochloride (Alzheimer's disease), as effective ultrasound-responsive agents. In 3D spheroids, combining low-intensity pulsed ultrasound with either drug significantly reduces viability compared with drug-only controls, and both combinations outperform temozolomide (TMZ), the current standard chemotherapeutic. Time-resolved responses reveal distinct kinetics: memantine produces strong early cytotoxicity (24 h) enhanced by ultrasound, whereas carboplatin shows delayed but pronounced cytotoxicity (72 h), also improved by ultrasound. Together, these results establish an integrated computational-experimental NAM that enables rapid repurposing of approved drugs as SDT sensitizers and provides a scalable framework for advancing GBM therapeutic discovery while reducing reliance on animal studies.

Hepatocellular carcinoma (HCC) is an aggressive malignancy with frequent recurrence and strong immune evasion. Programmed death ligand-1 (PD-L1) facilitates immune evasion by suppressing T-cell activity. Andrographolide (AD), a natural diterpenoid with anti-inflammatory, antiviral, and immunomodulatory properties, has demonstrated antitumor potential.

To evaluate whether prophylactic oral Lactobacillus supplementation reduces chemotherapy- and radiotherapy-associated diarrhea and helps preserve quality of life (QoL) in adults starting anticancer treatment.

The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase that plays a central role in regulating cell growth, differentiation, and survival. In non-small cell lung cancer (NSCLC) and several other malignancies, activating mutations within the EGFR kinase domain lead to persistent receptor activation and uncontrolled downstream signalling. Over the past two decades, X-ray crystallographic studies and structural data deposited in the Protein Data Bank have significantly enhanced our understanding of EGFR activation mechanisms, mutation-driven conformational changes, and inhibitor binding interactions. This review provides a critical evaluation of structural insights obtained from crystal structures of wild-type and mutant EGFR, with particular focus on clinically important mutations such as L858R, T790M, and C797S. These mutations induce specific alterations in activation loop positioning, αC-helix orientation, and ATP-binding pocket architecture, thereby influencing drug binding affinity and therapeutic response. The structural basis for the evolution of EGFR tyrosine kinase inhibitors-from first-generation reversible inhibitors to mutant-selective covalent agents-is discussed in relation to emerging resistance mechanisms. Although structural characterisation has substantially contributed to rational drug design, the ongoing development of resistance mutations highlights the need to integrate crystallographic data with tumour biology and resistance pathways to achieve more durable therapeutic strategies.

The ubiquitin-proteasome system (UPS) plays a central role in regulating protein homeostasis and degradation. Its dysregulation is closely associated with various diseases, including cancer. S-phase kinase-associated protein 2 (SKP2) is a key E3 ubiquitin ligase component of the UPS. It induces proteasome-mediated protein degradation or modulates substrate function by conjugating K48-linked or K63-linked ubiquitin chains to diverse target proteins. Recent studies have shown that the overexpression of SKP2 in several cancer types is correlated with poor clinical outcomes, underscoring its potential as a therapeutic target. Notably, emerging evidence has expanded the functional repertoire of SKP2 beyond cell cycle control to encompass metabolism, DNA repair, stemness, tumor microenvironment (TME) and immunotherapy response, positioning it as an increasingly attractive target for intervention. In this review, the oncogenic properties of SKP2 and its underlying mechanisms were elucidated in multiple cancer types. Moreover, we systematically summarized future directions for SKP2-targeted therapy.

The decision to rechallenge a patient with immune checkpoint inhibitor-associated acute kidney injury (ICI-AKI) remains one of the most challenging dilemmas in onco-nephrology. Although major guidelines affirm that rechallenge may be considered in selected patients, they uniformly acknowledge a critical gap: no validated tool currently exists to estimate an individual's risk of recurrence. Reported recurrence rates range from 16.5% to 44%, and the survival benefit of rechallenge is inconsistent across studies. In this review, we synthesize recent evidence on risk factors for ICI-AKI recurrence, including clinical parameters (acute kidney injury (AKI) severity, renal recovery status, extra-renal immune-related adverse events (irAEs), concomitant medications, and immune checkpoint inhibitor (ICI) regimen), pathological findings (acute tubulointerstitial nephritis (ATIN) with Banff scoring, and glomerular diseases), emerging biomarkers (urinary C-X-C motif chemokine ligand 9 (CXCL9)-to-creatinine ratio with an optimal cutoff of 269.5 ng/g, and serum soluble interleukin-2 receptor alpha (sIL-2Rα) with a cutoff of ≥1.75× the upper limit of normal (ULN)), genetic markers (the propionyl-CoA carboxylase subunit alpha (PCCA) variant rs16957301), and acute kidney disease (AKD). We translate this evidence into a practical, stepwise risk stratification framework that classifies patients into low-, intermediate-, and high-risk tiers through the sequential integration of clinical, pathological, and biomarker information. The biomarker cutoffs included in this framework-derived from diagnostic studies-are hypothesis-generating in the context of recurrence prediction and require prospective validation before clinical application. For each tier, we provide corresponding recommendations regarding rechallenge decisions, monitoring intensity, and prophylactic immunosuppression, while acknowledging the limited evidence supporting prophylactic corticosteroids in this setting. Finally, we discuss current controversies-including the optimal timing of rechallenge, racial differences that challenge model generalizability, and the unresolved role of prophylactic glucocorticoids-and outline future research priorities organized around clinical validation, biomarker development, mechanistic exploration, and integration of emerging technologies. This framework is designed for immediate clinical application across diverse settings, ranging from resource-limited primary hospitals to tertiary centers. By transforming empirical decision-making into evidence-based, individualized risk assessment, this review aims to guide precision rechallenge management for patients recovering from ICI-AKI.

This study aimed to assess the efficacy and safety of integrating programmed death-1 (PD-1) inhibitors with chemoradiotherapy (CRT) in the treatment of locally advanced nasopharyngeal carcinoma (LA-NPC), explore the optimal sequencing of immunotherapy, and to compare the short-term efficacy of different combination regimens during the induction phase.

For patients with locally advanced esophageal squamous cell carcinoma (ESCC) ineligible for surgery, definitive radiotherapy (RT) is the primary curative-intent treatment, yet outcomes remain suboptimal. The benefit of adding induction immunotherapy combined with chemotherapy prior to RT in this setting is unclear. This real-world study compared survival and safety between induction chemoimmunotherapy followed by RT and RT alone.

Bacillus Calmette-Guérin (BCG) is the standard adjuvant therapy for high-risk non-muscle-invasive bladder cancer (NMIBC); however, a substantial proportion of patients develop BCG-unresponsive disease with limited bladder-preserving options. The objective of this study was to determine whether combination immunotherapy provides superior clinical efficacy and safety compared with single-agent immunotherapy for patients with BCG-unresponsive NMIBC.

Previous studies have shown that locoregional therapy combined with systemic treatment provides survival benefits with manageable safety in patients with intermediate-to-advanced large hepatocellular carcinoma (HCC). However, the optimal treatment strategy for HCC beyond the up-to-7 criteria remains unclear because of the high tumor burden and recurrence risk. This study aimed to evaluate the efficacy and safety of transarterial chemoembolization (TACE) plus microwave ablation (MWA) followed by targeted immunotherapy in patients with HCC beyond the up-to-7 criteria.

In this study, we used Mendelian randomization analysis to explore the causal relationships between drug targets and cutaneous melanoma (CM) and subsequently screened for new drug targets for CM. In addition, we verified whether targeted drugs could inhibit the development of CM in CM cells by suppressing the expression of target genes.

The increasing resistance and adverse effects associated with conventional chemotherapeutic agents such as cisplatin have prompted the investigation of natural compounds that act synergistically with chemotherapy to combat cancer. This study investigates the cytotoxic effects of an aqueous extract of Artemisia vulgaris L. in conjunction with cisplatin on A549 human lung cancer cells. The research analyzes the phytochemical composition of the extract and its potential mechanisms of action by assessing apoptosis and autophagy. Cytotoxicity studies demonstrated a synergistic interaction between A. vulgaris and cisplatin. We utilized molecular docking to examine the interactions of the extract components with critical proteins involved in these processes.

Despite major advances in nanomedicine, therapeutic efficacy remains constrained by unfavorable host responses that influence nanotherapeutic retention, biodistribution, and activity. Biological strategies capable of enhancing nanomedicine performance through modulation of host-response pathways, rather than additional nanoparticle engineering, remain largely unexplored. Herein, we investigated whether a microbial levan produced by Weissella paramesenteroides could potentiate the therapeutic activity of a PEGylated β-cyclodextrin-capped benzimidazole-curcumin nanocomplex (BMPE-Cur) in an Ehrlich ascites carcinoma (EAC)-induced hepatic tumor model. Pharmacokinetic, biochemical, histopathological, angiogenic, immunological, molecular, and computational analyses were performed to evaluate therapeutic efficacy and explore underlying mechanisms. The co-administration of levan increased hepatic BMPE accumulation by 2.3-fold and significantly enhanced the therapeutic efficacy of BMPE-Cur, improving survival to 95.45% compared with 60.66% mortality in untreated tumor-bearing mice. Combination therapy produced 86% inhibition of angiogenesis, markedly suppressed tumor-associated biomarkers, oxidative stress, inflammatory mediators, and immunosuppressive cell populations, and restored hepatic function. These effects were accompanied by reduced expression of components of the TLR2/MyD88/NF-κB pathway, including an 80.05% reduction in MyD88 and a 78.93% reduction in NF-κB, together with 6.59-fold and 7.45-fold increases in FXR and FGF15 expression, respectively. Molecular docking supported potential interactions of BMPE, curcumin, and levan-derived structural motifs with TLR2, while isobolographic analysis demonstrated predominantly synergistic interactions across multiple biological endpoints. These findings support the potential of microbial levan as a promising biological potentiator of nanotherapeutic efficacy, with concurrent enhancement of hepatic nanocomplex retention and coordinated immunometabolic remodeling. More broadly, microbial exopolysaccharides may represent a promising class of host-response modulators, supporting a therapeutic paradigm in which optimizing the biological environment may complement conventional nanocarrier engineering to improve the performance of cancer nanomedicine.

Orally administered small-molecule programmed death ligand 1 (PD-L1) inhibitors may have the potential to improve patient outcomes in the treatment of a range of cancers compared with their antibody-based counterparts. A small molecule might achieve better tumor tissue penetration, and oral administration could significantly improve convenience and access for patients.

Drug sensitivity prediction is an important issue within the precision medicine field. IC50, which is the molar drug dose needed to decrease the viability of cells by half compared to the drug-free control, is the main pharmacodynamics parameter used for drug sensitivity analysis in large-scale pharmacogenomics screenings. Computational estimation of IC50s based on molecular and genomic factors significantly reduces costs associated with experiments for measuring cell viability and allows for accelerating the process of drug discovery. Traditional methods of IC50 calculation do not allow integrating the three-dimensional chemical structure of drugs and the biological context of particular cell lines, resulting in suboptimal model performance when using different pharmacogenomics data sources. In this work, we propose an innovative dual-branch approach based on Graph Isomorphism Network (GIN) drug representations coupled with a Multilayer Perceptron (MLP) for 50-dimensional ssGSEA pathway activities calculated from CCLE gene expression. After training on cell-line-drug pair combinations from the Genomics of Drug Sensitivity in Cancer 2 (GDSC2) dataset across various cancers, the proposed GIN+Pathway MLP model attains an R2 of 0.8553 and a Pearson Correlation Coefficient (PCC) of 0.9249 on the testing split of the same dataset. In a variant ablation study of six variants, we find that eliminating the pathway MLP component lowers the R2 value by more than 0.15, thus proving the importance of biological features in the two-branch model. The performance of our proposed model exceeds benchmark scores for models such as GraphDRP (PCC = 0.870, R2 = 0.756) and DeepCDR (PCC = 0.847, R2 = 0.720) when tested on the same GDSC2 dataset.

Aurora-A is a potential therapeutic target in prostate cancer. In this study, virtual screening identified four Aurora-A-targeting peptides, among which Peptide-1 showed the most favourable profile. Molecular docking and MST assays demonstrated that Peptide-1 had the lowest predicted binding free energy and the strongest binding affinity towards Aurora-A (Kd = 0.72 ± 0.04 μM). MD simulation, MM/PBSA, and free-energy landscape analyses indicated that the Aurora-A-Peptide-1 complex was conformationally stable and mainly driven by electrostatic interactions. MTT assays showed that Peptide-1 inhibited the proliferation of PC3, DU145, and NCI-H660 cells, with weaker activity in RWPE-1 cells. Aurora-A knockdown reduced cellular sensitivity to Peptide-1, supporting its target-dependent activity. qRT-PCR further showed increased p53 and p21 mRNA expression after Peptide-1 treatment in PC3/p53WT cells. These findings suggest that Peptide-1 may act as an Aurora-A-targeting peptide with antiproliferative activity in prostate cancer cells.

Cytotoxic chemotherapy remains integral to contemporary uro-oncology despite the rapid expansion of targeted therapy, antibody-drug conjugates, and immunotherapy. Its role is especially critical where therapeutic success depends on maintaining adequate dose intensity, most notably in metastatic testicular germ cell tumours and in cisplatin-based perioperative treatment for muscle-invasive bladder cancer. In metastatic prostate cancer and selected penile squamous cell carcinoma, taxane- and platinum-based regimens also retain clinical value but are constrained by hematologic, neurologic, renal, pulmonary, and gastrointestinal toxicities. This narrative review summarises current evidence and guideline recommendations for Common Terminology Criteria for Adverse Events (CTCAE)-guided management of chemotherapy toxicity across major uro-oncologic disease settings. A practical emphasis is placed on pretreatment risk stratification, cycle-by-cycle surveillance, supportive care, and intent-adapted treatment modification. Across tumour types, early recognition of grade 2 toxicity, urgent management of febrile neutropenia and organ toxicity, and thoughtful preservation of dose intensity when cure is realistic are the central management principles. In older, frail, immunosuppressed, heavily pretreated, or organ-limited patients, CTCAE grades must be interpreted against baseline reserve and cumulative toxicity.

Autoimmune thyroid diseases (AITDs), including Hashimoto's thyroiditis (HT) and Graves' disease (GD), affect approximately 2-5% of the global population. They are the most common organ-specific autoimmune disorders worldwide. Growing epidemiological and immunological evidence indicates that AITDs frequently coexist with immune-mediated dermatological diseases. These include atopic dermatitis (AD), psoriasis, alopecia areata (AA), vitiligo, and chronic spontaneous urticaria (CSU). Targeted immunotherapies have become central to the treatment of many immune-mediated skin diseases. Although these therapies are designed to act on specific immune pathways, they may also exert broader systemic immunomodulatory effects. However, thyroid function and thyroid autoantibodies are not routinely assessed in patients with immune-mediated dermatological conditions. This is also true for some patients with known or suspected AITDs. In this narrative review, we summarize the immunological overlap between cutaneous inflammation and autoimmune thyroid disease. We also discuss thyroid-related evidence for IL-4Rα inhibitors, IL-17 inhibitors, JAK inhibitors, IL-12/23 inhibitors, and immune checkpoint inhibitors (ICIs). Current evidence suggests that ICIs have the strongest established association with thyroid dysfunction. In contrast, the thyroid-related effects of dupilumab and ustekinumab are supported mainly by rare case reports. IL-17 inhibitors and selective IL-23p19 inhibitors may theoretically attenuate thyroid inflammatory pathways. However, this possibility has not yet been confirmed in clinical studies. Based on the available evidence, we propose a risk-stratified approach to thyroid surveillance across targeted immunotherapies. Routine thyroid monitoring is most strongly supported for ICIs. For patients at increased thyroid risk, selective assessment of thyroid function and thyroid autoantibodies may also be considered during treatment with dupilumab or ustekinumab. For oral JAK inhibitors, monitoring may be particularly relevant before treatment, during therapy, and after discontinuation because of the potential for immune rebound. Prospective studies are needed to define which patient subgroups would benefit most from thyroid surveillance during targeted immunotherapy.

Leptomeningeal metastases (LM) from melanoma are rare and associated with dismal outcomes. Intrathecal PD-1 antibody therapy has shown encouraging activity in LM. Radiotherapy may enhance tumor immunogenicity and potentially augment immune checkpoint blockade within the central nervous system. The efficacy and safety of combining intrathecal PD-1 antibodies with whole-brain radiotherapy (WBRT) in melanoma LM remain unclear.

Thyroid dysfunction is among the most frequent endocrine immune-related adverse events (irAEs) during PD-1/PD-L1 blockade, but whether baseline thyroid function and treatment-emergent thyroid dysfunction (TeTD) predict pathological response and survival after neoadjuvant immunochemotherapy in locally advanced gastric or gastroesophageal junction adenocarcinoma (LAGC/GEJC) remains unclear.