Lenalidomide is an immunomodulatory agent widely used in the treatment of multiple myeloma and is generally associated with a favorable safety profile. Although pigmentary alterations such as cutaneous hyperpigmentation and hair repigmentation have been reported, oral mucosal involvement remains poorly documented.

The TKI-targeted agent lapatinib has been applied in clinical oncology for the management of multiple malignancies. Nonetheless, its therapeutic benefit is restricted by cardiotoxic effects that endanger patient survival, and the underlying molecular basis remains unclear. The GSE146096 dataset containing transcriptomic profiles of lapatinib-exposed human cardiomyocytes was analyzed to identify ferroptosis-related differentially expressed genes (DEGs). Protein expression of selected targets was subsequently confirmed by Western Blot. Reactive oxygen species (ROS) accumulation, Fe²⁺ levels, and mitochondrial membrane potential in AC16 cells exposed to lapatinib were examined using confocal microscopy. A microplate reader was employed to quantify alterations in malondialdehyde (MDA) and glutathione (GSH) levels in cardiomyocytes. Eight ferroptosis-associated genes were identified in lapatinib-treated cardiomyocytes, including the canonical regulator GPX4. siRNA interference and Western Blot analyses demonstrated marked induction of ATF4 expression and significant suppression of GPX4 expression following lapatinib exposure in AC16 cells. CCK-8 assays indicated dose-dependent cytotoxicity. Confocal microscopy and transmission electron microscopy (TEM) revealed altered mitochondrial morphology accompanied by a reduction in mitochondrial membrane potential. Intracellular MDA levels increased substantially, whereas GSH levels declined, indicating lipid peroxidation and subsequent ferroptosis. Treatment with the ferroptosis inhibitor Ferrostatin-1 (Fer-1) or silencing of ATF4 expression effectively attenuated lapatinib-induced cytotoxicity. Lapatinib enhances ATF4 expression in cardiomyocytes, suppresses GPX4, triggers lipid peroxidation, induces ferroptosis, and thereby contributes to cardiotoxicity.

Sarcomas are rare, aggressive and unpredictable tumors that arise from mesenchymal tissues. Despite treatment, outcomes for advanced or metastatic cases remain poor. Anlotinib is a new oral tyrosine kinase inhibitor that blocks multiple angiogenic pathways and has shown encouraging results in solid tumors. This review aims to summarize and clarify the current evidence on anlotinib's role in treating sarcoma.

IntroductionImmune-related adverse events (irAEs) pose considerable challenges to the clinical application of immune-checkpoint inhibitors (ICIs). Noninfectious myocarditis/pericarditis is a class of ICI-associated adverse events with a high fatality rate in real-world settings. This study aimed to comprehensively assess noninfectious myocarditis/pericarditis adverse events associated with ICIs.MethodsReports of ICI-related noninfectious myocarditis/pericarditis AEs were extracted from the FDA Adverse Event Reporting System (FAERS) database. Disproportionality analysis was performed using the reporting odds ratio (ROR). Serious and non-serious outcomes of noninfectious myocarditis/pericarditis cases were compared using the Mann-Whitney U test or chi-squared test, and clinical priority was assigned to signals by scoring five features on a 0- to 10-point scale. Factors associated with reporting were explored based on stratified analyses.ResultsReports of noninfectious myocarditis/pericarditis AEs accounted for 1.67% of all ICI AE reports during the study period in the FAERS database. The median age of the patients was 70 years (interquartile range [IQR] 62-76), and 94.66% of reports had serious outcomes. Eight categories of noninfectious myocarditis/pericarditis AEs with positive RORs were identified. Noninfectious myocarditis/pericarditis AEs treated with ICIs were more frequently reported in male and older patients. Of note, 2, 3 and 3 AEs were identified as strong, moderate, and weak clinical priorities, respectively. The median time to onset (TTO) of strong, moderate and weak AEs for ICI treatments was 25 (IQR 14-61), 56 (IQR 24.50-116.25) and 124 (IQR 29-301) days, respectively. All disproportionality signals showed early-failure patterns, with the hazard of AE reporting decreasing over time.ConclusionsThis study suggests a significant disproportionality signal between ICIs and noninfectious myocarditis/pericarditis AEs, and the findings provide supporting evidence for clinicians in managing these AEs.

Pediatric oncology drug development remains uniquely challenging due to the rarity and biological heterogeneity of childhood cancers, ethical considerations in trial conduct, and the limited feasibility of large, randomized studies. Despite these barriers, recent years have seen a notable acceleration in the approval of oncology therapies for pediatric populations, driven by advances in molecularly targeted treatments, evolving regulatory requirements, and innovation in trial design. Reducing nonclinical data requirements and increasing the adaptation of model‑informed drug development approaches are also contributing to advances in pediatric oncology treatment by supporting dose selection, optimizing study design, and reducing unnecessary patient burden. In this review, recent regulatory requirements from the United States, the EU, and other key regions on pediatric oncology drug development are discussed. Thirty-three drugs with oncology indications in pediatric populations approved by the US FDA between 2018 and 2025 are reviewed. These approvals provide examples of how nonclinical and clinical data were generated with a focus on strategies for dose-finding and justification. Common challenges and considerations related to clinical operations and formulation development in pediatric populations and the emerging use of real-world data, external controls, and artificial intelligence/machine learning are also discussed.

Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common subtype, yet resistance to therapy remains a major clinical challenge. Up to 40% of patients carry PIK3CA mutations that activate PI3K/AKT/mTOR signaling and drive relapse, highlighting the need for more selective and tolerable targeted therapies.

Breast cancer has the highest incidence among malignant tumors in women worldwide. Although targeted therapy, chemotherapy, and endocrine therapy have achieved significant efficacy, acquired resistance remains a major challenge affecting patient prognosis. The present review systematically outlines five core mechanisms of resistance to breast cancer treatment, including overexpression of ATP‑binding cassette transporters that reduce intracellular drug accumulation; a hypoxic and immunosuppressive tumor microenvironment, together with breast cancer stem cells, that sustains stemness and impairs treatment response; DNA methylation, histone modifications, and non‑coding RNAs that mediate epigenetic reprogramming, leading to silencing of tumor suppressors or activation of resistance pathways; compensatory activation of multiple DNA damage repair pathways, including homologous recombination, non‑homologous end joining, base excision repair, nucleotide excision repair, and mismatch repair, which compromises the efficacy of chemotherapy and poly (ADP‑ribose) polymerase inhibitors; and metabolic reprogramming involving glycolysis, amino acid, nucleotide, and lipid metabolism that supplies tumor cells with energy, reducing equivalents, and biomass for proliferation, while simultaneously promoting immune evasion. Corresponding to these mechanisms, this review also summarizes potential therapeutic strategies, including combined targeted therapy, immunotherapy, and novel drug delivery systems. Therefore, a comprehensive dissection of the multidimensional networks mediating therapy resistance in breast cancer will provide both theoretical foundations and practical pathways for discovering novel biomarkers, optimizing precision combination therapies, and ultimately prolonging patient survival.

Tumor protein D52 (TPD52) family proteins are involved in the proliferation, survival and malignant progression of oral squamous cell carcinoma (OSCC). However, their roles in chemoresistance remain incompletely understood. The present study investigated the contribution of TPD52 family proteins to anticancer drug resistance, with particular emphasis on tumor protein D54 (TPD54). OSCC cells were treated with cisplatin, 5‑fluorouracil, or docetaxel (DTX), and the expression of TPD52 family members was examined. Gain‑ and loss‑of‑function analyses were performed to evaluate cell viability, apoptotic responses, cytochrome p450 (P450) and P‑glycoprotein (P‑gp) activities, protein expression, intracellular localization and membrane/cytosol distribution. Anticancer drug treatment increased the expression of TPD52, TPD53 and TPD54. Among these family members, TPD54 showed the strongest association with DTX resistance by attenuating the reduction in cell viability without affecting cell‑cycle progression. TPD54 overexpression attenuated DTX‑associated apoptotic responses and was associated with changes in apoptosis‑, ferroptosis‑, and autophagy‑related marker proteins. TPD54 expression had little effect on the activities of P450 3A4 or P450 1B1 but significantly increased P‑gp activity. Membrane/cytosol fractionation demonstrated increased membrane localization of endogenous P‑gp following TPD54 overexpression, whereas co‑immunoprecipitation and immunocytofluorescence analyses revealed an association and partial co‑localization between TPD54 and P‑gp. These findings suggest that TPD54 contributes to DTX resistance in OSCC cells through modulation of P‑gp localization and activity. The present study identifies TPD54 as a potential contributor to P‑gp‑associated chemoresistance and provides a basis for further investigation of the molecular mechanisms underlying multidrug resistance in OSCC.

Exportin 1 (XPO1) is a key nuclear export receptor that mediates the nuclear export of tumor suppressor proteins and growth‑regulatory mRNAs from the nucleus to the cytoplasm. In several types of cancer, XPO1 is overexpressed or hyperactivated, leading to aberrant cytoplasmic sequestration of key tumor suppressors such as p53, p21, p73, FOXO and Rb. This mislocalization abrogates their nuclear transcriptional functions, disrupting cell cycle arrest, apoptosis and DNA repair, thereby promoting uncontrolled proliferation, survival and therapy resistance. Targeting XPO1 with selective inhibitors of nuclear export (SINE) has emerged as a promising anticancer strategy. The present review systematically examines the molecular mechanisms of XPO1‑driven tumorigenesis and its rationale as a therapeutic target. The present review focuses on the clinical translation of SINE drugs, especially selinexor (KPT‑330), in hematologic and solid tumors, critically assesses the limitations of monotherapy and explores the mechanistic basis for synergistic combination strategies. Ongoing clinical trials and future directions to optimize therapeutic efficacy are also highlighted. Collectively, the present review aims to provide a comprehensive foundation for advancing basic and clinical research on XPO1‑targeted therapies.

Combination therapy with PD-1 and CTLA-4 inhibitors improves survival in advanced cancers but is associated with heightened toxicity. Whether this represents additive toxicity from each drug or a distinct synergistic profile remains unclear. This study utilized the FDA Adverse Event Reporting System (FAERS) to systematically characterize the toxicity landscape of dual PD-1/CTLA-4 blockade.

Esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive and lethal cancers, with high incidence and mortality rates in East Asia. Neoadjuvant chemotherapy (NC) has traditionally been the standard approach for improving resectability in ESCC, but its limited efficacy in achieving complete pathological responses and enhancing survival has driven interest in combining it with immune checkpoint inhibitors (ICIs), resulting in neoadjuvant chemoimmunotherapy (NIC). Based on randomized controlled trials (RCTs), this meta-analysis compares the risks and clinical benefits of NIC versus NC in resectable ESCC patients.

Thymidylate synthase (TYMS) is an established colorectal cancer (CRC) target. We evaluated whether conserved active-site architecture between human TYMS and the bacterial homolog TYSY KLEP7 could support early cross-species TYMS-axis lead discovery within the antifolate landscape. AlphaFold3, Chai-1 complex modeling, crystal-structure cross-validation, docking, ligand strain energy, MM-GBSA rescoring, and explicit-solvent MD were integrated to compare pocket states and prioritize antifolate-like Compound 8. Modeling indicated that Compound 8 preserves an acidic folate-groove anchoring motif while tolerating species- and ligand-induced pocket variation. Phenotypic assays showed dose-dependent inhibition of CRC cell viability with preliminary NCM460 selectivity, whereas antibacterial activity against K. pneumoniae was modest, with a MIC of 96 µM and bactericidal activity only at 4× MIC after 24 h. Target-axis assays supported TYMS/thyA engagement: siTYMS and AS-thyA reduced transcript levels, and Compound 8 inhibited crude-lysate TS activity with apparent AC50 values of 7.8 µM in HCT116 and 13.2 µM in K. pneumoniae. Overall, this work establishes an AI-enabled structure-to-phenotype framework and positions Compound 8 as an early antifolate-like TYMS-axis lead requiring purified-enzyme, ADME, safety, and antibacterial optimization studies.

Selenium, an essential trace element for humans, plays a critical role in maintaining physiological homeostasis; its deficiency has been associated with the onset of various pathological conditions. Selenium nanoparticles (SeNPs), the new selenium form, exhibit low toxicity and high bioactivity; nevertheless, bare SeNPs may easily aggregate and lose activity. Polysaccharides, as natural macromolecular compounds with various bioactivities, are considered ideal modifiers and stabilizers for SeNPs. This review summarizes the preparation methodologies employed in the fabrication of polysaccharide SeNPs, encompassing chemical reduction and biological synthesis. Subsequently, the structural characteristics and physicochemical stability profiles are critically analyzed. Furthermore, the biological functionalities, including antitumor, antioxidant, anti-inflammatory, immunomodulatory, hypoglycemic, and hypolipidemic activities, are comprehensively described, alongside their prospective industrial utility in food science, agricultural application, and pharmaceutical formulation. Finally, current research limitations are discussed, and future development directions are proposed, aiming to offer theoretical references and directions for developing polysaccharide SeNPs.

Chemoresistance constitutes a major cause of poor prognosis in advanced cervical cancer. Our previous studies have confirmed that Siglec-15 affects the progression of cervical cancer, whereas its role in regulating cervical cancer chemoresistance remains unexplored. This study investigates the role of Siglec-15 in cervical cancer chemoresistance and explores its mechanism. Siglec-15 expression and mitochondrial retrograde signaling levels were compared between parental and cisplatin-resistant cervical cancer cells. Lentiviral transfection was used to assess the functional effects of Siglec-15 modulation on the proliferation, apoptosis, and chemosensitivity of resistant cells. Further investigations were conducted to examine the effects of Siglec-15 on the mitogen-activated protein kinase (MAPK) signaling pathway, mitochondrial membrane potential, reactive oxygen species levels, and the expression of retrograde-related proteins. These in vitro findings were subsequently validated in vivo using a xenograft tumor model through immunohistochemistry, Terminal-deoxynucleotidyl transferase-mediated dUTP-nick-end labeling (TUNEL) assays, and western blotting. The results showed that Siglec-15 was markedly upregulated in cisplatin-resistant cervical cancer cells, correlating with enhanced mitochondrial retrograde signaling. Siglec-15 overexpression promoted cisplatin resistance and mitochondrial retrograde signaling, driving proliferation while inhibiting apoptosis. Mechanistically, Siglec-15 regulated mitochondrial retrograde signaling through activation of the MAPK pathway, thereby enhancing chemoresistance in drug-resistant cells. Elevated Siglec-15 expression enhances cisplatin resistance in cervical cancer cells by activating the MAPK pathway to promote mitochondrial retrograde signaling.

We present a Q-learning framework for optimizing chemotherapy dosing schedules in a stochastic finite-cell model of tumor evolution under drug-induced selection. The tumor consists of three competing subpopulations: a chemosensitive lineage, S, and two single-drug-resistant lineages, R_{1} and R_{2}, each resistant to one of two cytotoxic agents, C_{1} and C_{2}. Drug administration is formulated as a discrete action space in a finite-state Markov process, where the state is defined by the composition (S,R_{1},R_{2}) constrained by a fixed population size N. Tumor volume evolves according to a separate growth equation, with expansion rate proportional to the difference between the population-averaged fitness and a fixed microenvironmental baseline. Using Q-learning, we derive optimal dosing policies that balance therapeutic pressure with the evolutionary dynamics of resistance. The reward function is engineered to promote long-term coexistence among subpopulations, thereby delaying fixation of resistance by penalizing population imbalance. We analyze the structure of the optimal policies to (i) infer dominant evolutionary trajectories under treatment, (ii) quantify robustness to partial observability of both initial conditions and state updates, and (iii) construct simplified, symmetry-informed heuristics that approximate the full learned policy. Our results highlight the potential of model-free adaptive control strategies to steer tumor evolution away from drug resistance in the presence of biological stochasticity and information constraints.

Treatment-induced peripheral neuropathy (TIPN) significantly impairs patients' quality of life, compromises the treatment process, and adversely affects prognosis. The aim of this study was to evaluate the psychometric properties of the Treatment-induced Neuropathy Assessment Scale (TNAS) and establish cutpoints in Chinese patients with cancer.

Cancer stem-like cells contribute to innate tumour immunoresistance and an immunosuppressive tumour microenvironment, leading to poor responses to immune checkpoint inhibitors. Chemotherapeutic agents can elicit tumour immunogenicity by inducing immunogenic cell death to reinforce the therapeutic efficacies of immune checkpoint inhibitors, but suffer from inefficient immunogenic cell death activation in highly resistant cancer stem-like cells. Here we report an immunostimulatory lyotropic liquid-crystal-based lipogel for localized co-delivery of all-trans retinoic acid, a differentiation-inducing drug, and doxorubicin, an immunogenic-cell-death-inducing chemotherapeutic agent with distinct release kinetics. The lipogel is tailored to release the combinatorial drugs in a differential and sustained manner, which fulfils the requirement for enhanced drug synergism in promoting the immunogenic cell death of cancer stem-like cells. Local implantation of the immunostimulatory lipogel elicits an antitumour immune response that is further augmented by an immune checkpoint inhibitor to suppress tumour growth and metastasis, as well as to prevent post-surgical recurrence in murine models of high-stemness tumours.

A detailed molecular-level understanding of anticancer drugs is essential for improving therapeutic efficacy and guiding rational drug design. Everolimus (Afinitor), a clinically important inhibitor of the mammalian target of rapamycin (mTOR) pathway, is widely used in cancer therapy; however, a quantitatively grounded relationship between its spectroscopic characteristics and ligand-protein interactions remains insufficiently explored. In this study, an integrated experimental-computational approach was employed, combining FT-IR spectroscopy, UV-Vis spectroscopy, and molecular docking simulations. Spectroscopic analyses were used to characterise functional groups and electronic structure, while docking simulations were performed to investigate interactions with FK506 binding protein (FKBP12) and the FKBP-rapamycin binding (FRB) domain. FT-IR analysis revealed a high density of oxygen-containing functional groups, including hydroxyl and carbonyl moieties, with vibrational frequencies indicative of a strongly polarised electronic environment. Molecular docking demonstrated favourable binding affinities with FKBP12 (- 9.7 and - 9.6 kcal·mol⁻1) and the FRB domain (- 8.5 and - 6.6 kcal·mol⁻1). Detailed interaction analysis showed that these functional groups correspond to specific interacting atoms (e.g., O66, O67, O63, and O36), forming quantifiable hydrogen bonds (1.7-2.9 Å) and electrostatic interactions (~ 4.37 Å) with key residues such as TYR82, THR85, and GLU54. The UV-Vis absorption maximum at 278 nm corresponds to a HOMO-LUMO energy gap of 4.46 eV, indicating moderate electronic polarizability that supports charge redistribution during binding. The study establishes a quantitative and mechanistically grounded structure-spectra-interaction relationship, demonstrating that spectroscopic observables encode the local electronic environment governing ligand-protein interaction propensity. Binding affinity is shown to arise from a cooperative network of multiple non-covalent interactions enabled by the spatial distribution of functional groups. This integrated framework provides predictive insight into drug-protein interactions and offers a robust foundation for the rational design and optimisation of mTOR-targeting therapeutics.

Immune check-point inhibitors (ICIs) have outstandingly changed the treatment for lung cancer patients providing longer progression-free (PFS) and overall survival (OS). Immune-related adverse events (irAEs) counteract this success, and different biomarkers are broadly investigated to predict their appearance. Hematologic predictive biomarkers for irAEs are extensively studied to better prevent, monitor and treat irAEs. This is a retrospective exploratory-in-nature cohort study of lung cancer patients treated with ICIs in a tertiary level hospital in Romania, from 1 November 2017 until 1 August 2024. We evaluate 173 non-small cell lung cancer (NSCLC) patients treated with at least three cycles of ICIs and we investigate the association between Endocrine-irAEs and hematologic variables, such as neutrophil-to-lymphocyte ratio (NLR), absolute neutrophils, lymphocytes and eosinophils count. We also revise the literature and use an Artificial Intelligence (AI) technique to interpret our endpoints. We identify a statistically significant correspondence between NLR value before ICIs initiation and all-irAEs [odds ratio (OR) 0.877, 95% confidence interval (CI) 0.763-0.979, p = 0.036], but not for Endocrine-irAEs (OR 0.898, 95% CI 0.781-1.031, p = 0.081). While significant barriers for identifying the patients at risk of developing irAEs are still present, the implementation of truly relevant and useful biomarkers remains challenging. NLR might be a useful and easy to assess tool in real-life clinical settings, but more research is needed to validate its prediction value in Endocrine-irAEs onset.

Identifying drug-induced cancer cell death pathways is crucial for understanding the mechanisms of drug action. However, traditional biological experimental methods are limited by their time-consuming nature and high cost. This aim of this study is to develop classification models that can predict apoptosis and pyroptosis in cancer cells, combining Raman spectroscopy with machine learning algorithms.