Anti-PD-1 treatment has shown clinical benefit in malignant cancers. However, EGFR-mutant (EGFR-MT) lung adenocarcinoma, an immune-cold tumor, shows poor response to this immunotherapy. This scenario is associated with elevated levels of B7-H4, an immune checkpoint demonstrating CD8+ T cell inhibition activity. Our previous study has revealed that deubiquitinase USP2a could stabilize B7-H4 protein. Therefore, we further explore whether USP2a inhibition could remodel immune-cold microenvironment in this study. First, we confirmed that USP2a inhibitors effectively promoted proteasomal degradation of B7-H4 through blocking its deubiquitination process. To rule out the possiblity that USP2a might directly inhibit EGFR MT endocytosis so as to inhibit B7-H4 expression,we investigated the effect of USP2a inhibitor ML364 on EGFR mutants protein levels. It showed that ML364 did not inhibit EGFR mutant protein levels. ML364 could directly inhibit tumor cell proliferation in vitro. In immune-deficient nude mice ML364 inhibited tumor growth through inhibiting USP2a substrates Cyclin D1 and MDM2. In immune-competent C57BL/6 mouse model, ML364 could downregulate B7-H4 level thereby repress tumor growth through remodeling immune-cold microenvironment. Finally, we proved that ML364 could sensitize tumor to anti-PD-1 therapy in immune-competent mice. Immunohistochemical staining analysis showed that ML364 could inhibit B7-H4 expression, thereby enhanced Qa-1b (homolog of HLA-E in mouse) expression and CD8+ T cell infiltration. This study proved that inhibition USP2a could suppress tumor growth through two mechanisms: directly inhibiting tumor cell proliferation and remodel immune-cold microenvironment. Therefore, inhibiting USP2a could sensitize tumor to anti-PD-1 therapy.

Immune checkpoint inhibitor (ICI)-related pneumonitis (ICI-pneumonitis) is a serious complication, whose clinical course and optimal management strategies remain inadequately elucidated. This study clarified whether post-pneumonitis ICI continuation is safe and feasible, identified risk factors for fatal outcomes or successful continuation, and assessed whether findings from patients with lung cancer can be generalized to those with other malignancies.

The degradation of overexpressed proteins has emerged as a promising strategy for halting disease progression, particularly in cancer. Traditional small-molecule drugs often face limitations in the elimination of pathogenic proteins, leading to the development of targeted protein degradation (TPD) approaches. A prominent strategy for TPD is the proteolysis targeting chimaera (PROTAC) which harnesses the ubiquitin proteasome system, the cell's innate degradation machinery, to degrade proteins of interest (POIs). In this review, we will focus on the design and synthetic strategies that led the advancements of PROTACs as a cancer therapy for the targeted degradation of poly ADP-ribose polymerases (PARPs), glutathione peroxidase 4 (GPX4) and epigenetic regulators. We also aim to address the prevailing challenges in PROTAC development and clinical translation, namely target diversification, oral bioavailability, stability, degradation efficiency, and optimising multivalent binding.

Immune checkpoint inhibitors (ICIs) can induce immune system activation and cause immune-related adverse events (irAEs). This study aimed to assess the incidence and management of irAEs in thymoma patients with preexisting MG who received ICI therapy.

The properties and meridian affinities of Chinese herbal medicine are closely associated with their therapeutic efficacy. This review focuses on approved antitumour Chinese medicines listed in the Pharmacopoeia of the People's Republic of China (2020 Edition, Volume I), highlighting their key components. Statistical methods were used to analyse the properties, flavours and channel tropisms of antitumour traditional Chinese medicine (TCM), including both proprietary formulations and commercially available individual herbs. Distinctive patterns were identified by comparing herb profiles with contemporary experimental studies on antitumour TCM. Analysis revealed that bitter-cold herbs represented the highest proportion of antitumour TCM, with most showing tropism towards the liver channel. These findings provide a reference framework for antitumour drug development, indicating that bitter-cold herbs merit priority as candidate ingredients.

Diabetic macular edema (DME) remains a leading cause of vision loss in the working-age population, yet its management is undergoing a fundamental paradigm shift from high-frequency anti-VEGF monotherapy toward more durable and multi-mechanism therapeutic strategies. This narrative review provides an up-to-date overview of the pharmacological landscape of DME as of 2025, synthesizing evidence from pivotal clinical trials, recent regulatory approvals, and available real-world outcomes. We examine the transition toward injection-sparing approaches and discuss the clinical rationale for targeting alternative biological pathways beyond VEGF inhibition, including angiopoietin-2 (eg, faricimab), the plasma kallikrein-kinin system, and tyrosine kinase-mediated signaling. Collectively, emerging evidence suggests that the future management of DME will be defined by a paradigm shift toward injection-sparing, multi-pathway therapeutic strategies, extending beyond short-term fluid suppression toward a more personalized, precision-medicine framework that prioritizes long-term durability, safety, and functional outcomes.

This retrospective study was to identify the outcomes and safety of anlotinib combined with PD-1 blockades in patients with metastatic esophageal squamous cell carcinoma (ESCC).

Acute myeloid leukemia (AML) remains the most aggressive form of leukemia, underscoring the urgent need for novel treatment strategies. Drug repurposing offers a promising approach to accelerate drug development process. Cardiac glycosides (CGs), traditionally used for heart conditions, have shown potential for AML therapy. As leukemic stem cells (LSCs) are key contributors to AML relapse and chemotherapy resistance, this study aims to elucidate the potential shared mechanisms of proscillaridin (PSN) and ouabain (OUA), two CGs with anti-LSC activity, focusing on their multitarget effects-an emerging strategy in cancer therapy.

Venetoclax (VEN), a selective B-cell lymphoma 2 (BCL-2) inhibitor, is used in pediatric hematologic malignancies. Research on individualized VEN therapy in Chinese pediatric patients remains limited. This study aimed to develop a population pharmacokinetic (PPK) model in Chinese pediatric patients, identify covariates influencing pharmacokinetics, support personalized dosing, and explore exposure-efficacy relationships in pediatric acute myeloid leukemia (AML).

Chemodynamic therapy (CDT) has emerged as a promising cancer treatment strategy leveraging tumor microenvironment conditions to generate reactive oxygen species (ROS) through Fenton-type reactions. This study reports the synthesis, in-depth characterization, and biological evaluation of novel manganese-based zeolitic imidazolate framework (ZIF) nanoparticles, ie, Mn-rods, as a carrier-free potential CDT platform with exceptionally high manganese loading.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and serious side effect of cancer treatment. Studies have shown that there is significant sexual dimorphism in animal models, molecular mechanisms and drug treatment responses of CIPN-related pain. This review systematically explores these sex differences in CIPN.

In this study, a series of novel thiadiazole derivatives (7a, 7b, 9a, 9b, and 9c) were rationally designed as potential VEGFR-2 inhibitors using a pharmacophore-guided strategy. The compounds were synthesized and assessed for their antiangiogenic and anticancer effects. Among them, compound 9b showed the strongest VEGFR-2 inhibition (IC50 = 0.030 ± 0.001 μM), outperforming the reference drug Sorafenib. Cytotoxicity tests revealed that 9b was highly effective against MCF-7 breast cancer cells (IC50 = 8.06 ± 0.7 μM) while exhibiting minimal toxicity toward normal WI-38 cells. Flow cytometry demonstrated that 9b induced significant G2/M cell cycle arrest and increased apoptosis, supported by molecular data showing upregulation of caspase-3 and Bax and downregulation of Bcl-2, indicating activation of the intrinsic apoptotic pathway. Extensive in silico studies-including molecular docking, 200 ns molecular dynamics simulations, interaction mapping, principal component analysis of trajectories, and free energy landscape analysis-confirmed that 9b binds stably and efficiently within the VEGFR-2 active site. Overall, these results highlight compound 9b as a promising VEGFR-2-targeted antiangiogenic agent with potent enzymatic and cellular activity, favorable selectivity, and mechanistic validation through combined experimental and computational approaches.

Chemotherapy-related toxicity has been associated with body composition, yet there is no consensus on which CT-derived muscle parameter or handgrip strength (HGS) best predicts toxicity in pediatric cancer patients. This study evaluated whether CT-derived body composition parameters and nutritional status independently predict early chemotherapy-related infections and hematologic toxicity in children and adolescents with cancer. In this prospective observational cohort, patients aged 7-18 years undergoing chemotherapy with available CT/PET-CT scans were included. Anthropometric data (weight, height, arm circumference, triceps skinfold thickness) and HGS were collected. At the third lumbar vertebra (L3), skeletal muscle mass (SMM), skeletal muscle index (SMI), total adipose tissue, and muscle radiodensity were measured; psoas area was assessed at L4. Associations were analyzed using χ2 tests and logistic regression adjusted for sex, age, tumor stage, and type. Forty-eight patients were included (mean age 12.6 ± 3.3 years; 64.6% male); 64.6% had hematologic malignancies and 53.6% had advanced disease. Most were classified as having normal nutritional status (50-64.6%). Hematologic (100%) and gastrointestinal (85.4%) toxicities were most frequent. Low SMM and SMI were correlated with a higher risk of infection (OR 4.20; 95% CI 1.23-14.27 and OR 3.92; 95% CI 1.17-13.20, respectively) and fever (OR 4.05; 95% CI 1.21-13.54 and OR 5.82; 95% CI 1.67-20.25, respectively). After adjustment, only low SMI remained independently associated with fever (OR 4.74; 95% CI 1.09-20.61; p = 0.038).

LINKER-MM1 (NCT03761108) is a Phase 1/2 study of linvoseltamab, a human BCMA×CD3 bispecific antibody for patients with relapsed/refractory multiple myeloma (RRMM) who are triple-class exposed (TCE) with ≥ 3 prior lines of therapy (3L+), or triple-class refractory (TCR). To contextualize efficacy data from LINKER-MM1, the Phase 2 linvoseltamab 200 mg cohort (N = 105) was compared with an international external control arm (ECA) comprising 203 patients from participating International Myeloma Working Group sites who met LINKER-MM1 eligibility criteria based on chart reviews. The ECA reflected real-world standard-of-care (RW SOC). An independent data review committee assessed data relevance, quality, and cohort comparability, while a separate independent central review committee evaluated response data. Inverse probability of treatment weighting was used to balance baseline characteristics between the linvoseltamab arm and the ECA. Linvoseltamab had a higher objective response rate (weighted odds ratio 3.0 [95% confidence interval (CI): 1.9-4.1]) and longer median progression-free survival (weighted hazard ratio [wHR] 0.33 [95% CI: 0.28-0.40]), time to next treatment (wHR 0.34 [95% CI: 0.29-0.44]), and overall survival (wHR 0.72 [95% CI: 0.58-0.98]) than RW SOC. These findings highlight linvoseltamab's potential as an effective treatment for 3L+ and TCE/TCR RRMM.

In this study, we investigated the anticancer activity of cedrol, a sesquiterpene alcohol, in the human epidermoid carcinoma cell A431 and in epidermal carcinoma 3D skin. Although various physiological activities of cedrol have been reported, the anticancer effect of cedrol in epidermal carcinoma and its molecular mechanisms still remain unclear. Cedrol exhibited significant cytotoxicity in A431 cells in a concentration-dependent manner and reduced the expression of minichromosome maintenance (MCM) proteins. To elucidate the underlying anticancer mechanisms, cell cycle and apoptosis analyses were performed. Cedrol induced dose-dependent G0/G1 phase arrest in A431 cells after 24 h of treatment, accompanied by induction of p53 and p21 and reduction of cyclin E and CDK2. After 48 h of cedrol treatment, apoptosis was observed, as demonstrated by the increase in SubG1 population and Annexin V-positive apoptotic cells using flow cytometry. Cedrol-induced apoptosis was further confirmed by increased expression of the death receptor Fas and the pro-apoptotic protein Bax, decreased expression of the anti-apoptotic protein Bcl-2, release of cytochrome c, and PARP cleavage following caspase activation, indicating apoptosis occurred via both intrinsic and extrinsic pathways. In addition, the cytotoxic effect of cedrol was also observed in an epidermal carcinoma 3D skin constructed using A431 cells, but not in a normal 3D skin constructed using HaCaT cells. Taken together, these findings suggest that cedrol may serve as a novel anticancer therapeutic candidate for epidermal carcinoma and propose that the epidermal carcinoma 3D skin model can be utilized in nonclinical trials.

Poly(ADP-ribose) polymerase (PARP) inhibition (PARPi) is a precision medicine strategy in advanced prostate cancer, with the greatest benefit seen in a subset of patients with homologous recombination repair (HRR) gene alterations. Combination approaches may expand activity beyond HRR-altered disease. We conducted a phase 2 study of the PARP inhibitor olaparib in combination with the anti-PD-L1 antibody durvalumab in an HRR-unselected population of men with metastatic castration-resistant prostate cancer (mCRPC).

Poly-ADP ribose polymerase inhibitors (PARPi) are well-known to treat tumors that are deficient in homologous recombination (HR) DNA repair. However, PARPi can treat breast cancer gene (BRCA) wild-type tumors, the mechanisms behind which are not fully elucidated. We previously reported that tumor-intrinsic programmed death ligand-1 (PD-L1) signals promote HR, and that genetic tumor PD-L1KO impairs HR and sensitizes tumors to PARPi. Despite significant PARPi efficacy in PD-L1KO tumors, US Food and Drug Administration (FDA)-approved anti-PD-L1 antibodies did not improve PARPi. Thus, additional clinically translatable approaches to target tumor-intrinsic PD-L1 signals to elicit PARPi sensitivity are needed.

Propolis is a complex natural product used in functional foods and nutraceuticals, and its bioactivity depends on its botanical origin and processing. In this study, we employed a cold-ethanol extraction method on Polish propolis to produce wax-free polyphenol-rich extracts while preserving heat-sensitive compounds. UHPLC-DAD-ESI-IT-MS profiling identified 72 compounds in the extracts, predominantly flavonoids and caffeic acid esters (e.g., CAPE), which is consistent with a poplar-type propolis profile. The cold-extracted propolis exhibited potent anti-melanoma activity in vitro against human melanoma cell lines (A375 and SK-MEL-3), with minimal impact on normal skin fibroblasts at similar concentrations. Both extract variants (prepared using 75% and 80% ethanol) exhibited dose-dependent cytotoxic and antiproliferative effects on melanoma cells, with the 75% ethanol extract consistently demonstrating greater potency. At 75 μg/mL, the 75% extract reduced SK-MEL-3 cell viability to ∼20%, whereas the viability remained ∼60% with the chemotherapeutic control (etoposide). In a wound-healing assay, 25 μg/mL of the 75% extract inhibited melanoma cell migration as effectively as an equal concentration of etoposide, indicating its strong anti-metastatic potential. Propidium iodide/Hoechst staining confirmed that the propolis extract induced melanoma cell death. This study is the first to correlate the region-specific chemical profile of Polish propolis with its comprehensive anti-melanoma effects. Overall, these findings demonstrate that cold-ethanol extraction yields a highly bioactive polyphenol-rich propolis extract, highlighting its potential as a valuable ingredient in functional foods and in the nutraceutical industry.

The Mini-Chromosome Maintenance (MCM) 2-7 helicase complex is a pivotal component of the eukaryotic DNA replication machinery and an emerging therapeutic target in oncology due to its role in replication licensing and genomic stability. Despite its biological importance, few small-molecule inhibitors have been rationally developed for this complex, particularly against human MCM2. In this study, we employed a structure-based virtual screening strategy combined with molecular dynamics (MD) simulations, MM-PBSA binding free energy calculations, and comprehensive pharmacokinetic modeling to identify novel quinolone-based inhibitors targeting the AAA+ ATPase domain of MCM2. Twelve rationally designed compounds were docked against a refined AlphaFold3-derived structure of human MCM2. Ligands 1, 7, and 8 exhibited the strongest binding affinities (up to -8.66 kcal/mol), outperforming the reference compound ciprofloxacin. MD simulations over 100 ns revealed that Ligand 8 most effectively stabilized the OB-fold and ATPase domains, while Ligand 1 formed a highly persistent hydrogen bond network (mean 7.2 ± 1.8 bonds). MM-PBSA energy decomposition showed Ligand 1 possessed the most favorable binding free energy (-51.27 ± 8.46 kJ/mol), attributed to strong polar solvation contributions. In silico ADMET predictions confirmed low mutagenic risk, extended half-life (≥3h), and favorable drug-likeness, although oral bioavailability remained limited. Collectively, this work establishes a robust computational pipeline for helicase-targeted drug design and identifies promising MCM2 inhibitors with superior binding and pharmacological properties, offering mechanistic insight into ligand-induced stabilization of replication machinery and supporting further in vitro and in vivo exploration as anticancer therapeutics that exploit replication stress vulnerabilities.

Standard adjuvant chemotherapy for stage III colon cancer consists of a fluoropyrimidine-plus-oxaliplatin regimen. Whether the addition of atezolizumab (an anti-programmed death ligand 1 agent) to a modified FOLFOX6 regimen (fluorouracil, oxaliplatin, and leucovorin; called mFOLFOX6) would improve outcomes in patients with stage III colon cancer with mismatch repair-deficient (dMMR) status is unclear.