Given the high incidence of hepatocellular carcinoma (HCC) and its limited therapeutic options, and building on our previous work on anti-HCC sesquiterpenoid dimers, a series of natural product-like guaianolide-eudesmanolide dimers were designed and synthesized as potential anti-HCC agents in this study. Among them, compound 1 showed significantly antihepatoma effects on HepG2, Huh-7, and SK-Hep-1 cells with IC50 values of 5.6, 4.8, and 4.6 μM, respectively; induced cell cycle arrest and apoptosis; and inhibited the migration of HCC cells. Bioinformatic analysis and experimental validation indicated that compound 1 directly targeted NEURL1B, which was further established as a critical regulator of HCC proliferation and migration. Mechanistically, compound 1 bound to Arg422 within the NHR2 domain of NEURL1B, triggering its autoubiquitination and degradation, which stabilized DLL1 by suppressing its ubiquitination and ultimately attenuated the Notch signaling pathway. In vivo experiments showed that compound 1 (60 mg/kg) inhibited tumor weight up to 69% in SK-Hep-1 xenograft nude mice, which was comparable to that of sorafenib (67%) at the same dose. This study revealed that the previously unrecognized oncogenic role of NEURL1B acted as upstream of DLL1 in HCC, and suggested that compound 1 might be an antihepatoma candidate that inhibited Notch signaling by disrupting the NEURL1B-DLL1 interaction.

Enzalutamide is a potent androgen receptor (AR) inhibitor widely used for the treatment of castration-resistant prostate cancer (CRPC). However, the development of drug resistance severely limits its therapeutic efficacy, and the underlying mechanisms remain poorly understood. We have demonstrated that decorin (DCN), a suppressor of prostate cancer (PCa) progression, is significantly down-regulated in enzalutamide-resistant PCa cells. Therefore, we hypothesized that diminished expression of DCN contributes to enzalutamide resistance in PCa. In this study, we found that DCN was decreased in enzalutamide-resistant LNCaP cells (LNCaP-ER), which exhibited resistance to ferroptosis. Consistently, DCN was significantly reduced in high-grade PCa and CRPC tissues, as well as in those with poor clinical survival outcomes through integrative analysis. Moreover, DCN overexpression re-sensitized LNCaP-ER cells to enzalutamide by activating ferroptosis. What's more, DCN overexpression significantly inhibited tumor growth and metastasis of LNCaP-ER cells in vivo under enzalutamide-treated conditions, in a ferroptosis-dependent manner. Mechanistically, DCN activated calcium-dependent Protein Kinase C Beta II (PKCβII), thereby enhancing phosphorylation of long-chain acyl-CoA synthetase 4 (ACSL4) to regulate lipid remodeling and promote ferroptosis. In addition, enzalutamide-mediated AR nuclear translocation negatively regulates DCN transcription. In conclusion, promoting DCN-mediated ferroptosis might be a potential strategy for enhancing the sensitivity of enzalutamide in PCa cells. This study delineates a novel mechanism by which DCN downregulation suppresses ferroptosis and drives enzalutamide resistance in CRPC.

Chemodynamic therapy (CDT) holds significant promise for tumor-selective treatment; however, its therapeutic performance is frequently hampered due to the insufficient endogenous hydrogen peroxide (H2O2) and strict Fenton reaction conditions. Herein, an innovative cascade-amplified nanoreactor is synthesized through a solvothermal approach, with F127 serving as a structure-directing soft template to construct hollow manganese ferrite nanoparticles (HMF), further coated with polydopamine (HMFP) and loaded with glucose oxidase (GOx) (HMFPG). Within the tumor microenvironment, glucose is oxidized by the released GOx to form gluconic acid and H2O2, inducing tumor starvation while generating additional H2O2 for the Fenton reaction. Simultaneously, Mn2+ catalyzes H2O2 decomposition to produce O2, which further promotes GOx-mediated glucose oxidation and sustains the cascade catalytic reaction. The self-supplied H2O2 and O2 effectively enhance the dual catalytic centers (Fe3+/Mn2+)-mediated Fenton and Fenton-like reactions, producing abundant ·OH radicals. Moreover, the photothermal effect of HMFP accelerates the Fenton reaction rate, establishing a positive feedback process for CDT. Both in vitro cellular and in vivo animal studies demonstrate that the integrated CDT/photothermal therapy (PTT)/starvation therapy (ST) achieves remarkable antitumor efficacy. Overall, this self-sufficient nanoplatform (HMFPG) significantly boosts CDT performance by integrating dual catalytic centers, autonomous H2O2/O2 generation and photothermal amplification. This breakthrough provides a novel nanoplatform and promising conceptual advancement for enhanced multimodal tumor therapy.

Cellular stresses regulate transcriptional readthrough, whereby RNA polymerase II elongates past a gene's polyadenylation cleavage site without RNA cleavage. Readthrough has been reported in several cancer types. Here, we use long-read sequencing of nascent RNA to quantify transcriptional readthrough in chronic myeloid leukemia (CML) cells and characterize early responses to the targeted therapeutic, imatinib. We show that the amount, length, and gene specificity of readthrough increase within 1 hour, before gene expression and alternative splicing alterations emerge. Notably, imatinib-dependent messenger RNA (mRNA) isoform changes involved "readthrough chimeras," in which exons from an upstream gene are alternatively spliced to exons in a downstream gene. Altered mRNA isoforms and chimera levels were detected in imatinib-resistant K562 cells as well as cells of patients with CML. Thus, imatinib can provoke a cascade of early changes to transcription and splicing fidelity that may lead to longer-term adjustments in gene expression, cancer cell differentiation, and the development of therapy resistance.

Talquetamab (TAL), a first-in-class bispecific antibody targeting GPRC5D and CD3, has demonstrated high efficacy in heavily pretreated relapsed and refractory multiple myeloma (RRMM), achieving response rates of approximately 70%. However, TAL is frequently associated with on-target, off-tumor oral toxicities.

The genus Artemisia (family Asteraceae) is widely recognized for its medicinal properties, among which artemisinin is the most notable, historically serving as a key antimalarial agent. Accumulating evidence now highlights the significant anticancer potential of Artemisia species, with bioactive compounds such as artemisinin and its derivatives exhibiting promising activity across multiple cancer types. This review provides a comprehensive overview of the molecular mechanisms underlying the anticancer effects of Artemisia-derived compounds, including apoptosis induction, cell cycle arrest, and oxidative stress modulation. In addition, it examines their therapeutic efficacy in preclinical in vivo models and summarizes findings from early-phase clinical trials. Despite encouraging preclinical results, challenges such as drug resistance, limited bioavailability, and barriers to clinical translation remain.

Small-molecule BAX activators can trigger intrinsic apoptosis directly and thus hold unique potential as a new class of anticancer therapy. Current arsenal of known BAX activators is very limited. In this work, we first identified an active hit with micromolar binding affinity to BAX through virtual screening, and then replaced the complex hexahydrocyclopenta[c]quinoline moiety in its structure through scaffold hopping. Multiple rounds of structural optimization led us to finally focus on the compounds with a phenylpyrrole core moiety. The optimal compound (27c) exhibited selective binding to BAX with submicromolar binding affinity (IC50 = 300 nmol/L). Functional assays validated that 27c activated BAX in living cells and consequently induced intrinsic apoptosis. Cell viability tests indicated that 27c was effective not only against hematologic cancers but also drug-resistant solid tumors when combined with a BCL-XL inhibitor. Although the in vivo PK properties of 27c revealed certain limitations such as relatively short half-life and rapid clearance, its novel structural scaffold and compelling in vitro potency position it as a promising starting point for future development.

Astragalus membranaceus, a Qi‑tonifying herb widely used in traditional Chinese medicine, has emerged as a promising adjuvant for female‑predominant malignancies, including breast, ovarian and cervical cancers. Its major bioactive constituents, Astragalus polysaccharides (APS) and astragalosides (AST), exert multitarget antitumor activities and are widely used as complementary agents in clinical oncology. Nevertheless, key mechanistic gaps persist, particularly regarding the crosstalk among the PI3K/Akt/mTOR, Wnt/β‑catenin, JNK/MAPK and TGF‑β/Smad pathways, as well as the subtype‑ and context‑dependent regulation of molecular effectors governing programmed cell death, epithelial‑mesenchymal transition and immune reprogramming. This uncertainty constrains biomarker discovery and the rational design of combination regimens, thereby limiting the predictability of clinical benefit. The present review systematically collates current research on the molecular mechanisms and signaling networks through which APS and AST modulate breast, ovarian and cervical cancer biology. Available data indicate that these compounds suppress tumor initiation and progression by inhibiting proliferation, inducing programmed cell death, attenuating invasion and metastasis, reshaping antitumor immunity and macrophage polarization, and potentiating chemotherapeutic efficacy while mitigating treatment‑related toxicity. Overall, these insights aim to provide a mechanistic rationale for the clinical integration of A. membranaceus as an adjuvant therapy in gynecological and breast cancers, to bridge traditional Chinese medicine with contemporary pharmacology, and to support the development of individualized, integrative therapeutic strategies for breast, ovarian and cervical cancers.

Castration-resistant prostate cancer (CRPC) remains a significant therapeutic challenge with limited effective treatment options. We identified retinoid X receptor γ (RXRγ) as a critical regulator of CRPC cell proliferation, highlighting it as a previously unrecognized and tractable target for therapeutic intervention. However, no RXRγ-selective modulators have been reported. Herein, we utilized the PROTAC approach to develop WCF-598 as a potent RXRγ degrader, which exhibits preferential degradation of RXRγ over RXRα and RXRβ isoforms. WCF-598 promoted efficient RXRγ degradation through the ubiquitin-proteasome system, leading to robust antiproliferative activity in CRPC models. In vivo, WCF-598 induced significant tumor regression in 22Rv1 xenograft-bearing mice without observable toxicity. Notably, WCF-598 also exhibited a secondary activity by degrading androgen receptor splice variant 7 (AR-V7), a clinically relevant driver of therapy resistance in CRPC. These results establish WCF-598 as a specific chemical probe for investigating the function of RXRγ in CRPC and potentially other RXRγ-related diseases.

We report a case of a 79-year-old woman with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer who developed secondary aplastic anemia during treatment with the EGFR tyrosine kinase inhibitor (TKI) osimertinib. In the 23rd week of osimertinib treatment, the patient developed pancytopenia accompanied by fatty bone marrow. Discontinuation of osimertinib and initiation of treatment with cyclosporine A (100 mg/day) and eltrombopag (25 mg/day), a thrombopoietin receptor agonist, resulted in hematological recovery. Gefitinib, a first-generation EGFR-TKI, effectively suppressed the progression of lung cancer without any recurrence of pancytopenia for four months. However, rechallenge with osimertinib upon disease progression resulted in the recurrence of pancytopenia. This case suggests that osimertinib can cause severe hematological toxicity, such as aplastic anemia, possibly through an immune-mediated mechanism independent of EGFR inhibition.

One-carbon metabolism is essential for nucleotide biosynthesis and redox homeostasis, and its key enzymes, MTHFD2 and MTHFD1, are aberrantly activated in diverse cancers, particularly acute myeloid leukemia (AML). Herein, we solved the X-ray crystallography of the reported MTHFD inhibitor DS18561882 bound to MTHFD2 and performed systematic structure-activity optimization, leading to the identification of a highly selective MTHFD2 inhibitor (compound 31) and a dual MTHFD1/2 inhibitor (compound 34). Cocrystal structural analysis revealed that subtle modifications of the aminosulfonamide motif dictate isoform selectivity by reshaping hydrogen bond and hydrophobic networks within the MTHFDs active site. Notably, the dual inhibitor 34 exhibited superior antiproliferative activities across AML cell lines and induced marked tumor regression in MOLM-13 xenograft models with minimal toxicity, outperforming the reference compound DS18561882. Our findings establish rational design principles for isoform-selective and dual MTHFD1/2 inhibitors and highlight a combined MTHFD1/2 blockade as a promising therapeutic strategy for AML.

Psoriasiform eruption is an uncommon cutaneous immune-related adverse event (irAE) associated with anti-PD-1 therapy, and its rapid recurrence upon switching to a different anti-PD-1 agent is a scarcely documented phenomenon. We report the case of a 59-year-old man with stage IIB lung adenocarcinoma who developed a pruritic, scaly eruption after his fourth cycle of pembrolizumab. Histopathological examination confirmed a diagnosis of grade 2 psoriasiform dermatitis according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The initial episode was resolved with systemic corticosteroids. However, upon switching anti-PD-1 therapy to tislelizumab, a similar but more widespread eruption recurred rapidly within a week. The recurrence was successfully managed with topical corticosteroid and antihistamines, and the anti-PD-1 therapy was subsequently discontinued. During the 3-year follow-up after discontinuation, the patient's skin lesions resolved completely with no recurrence, and no tumor progression was observed. The reduced latency of psoriasiform dermatitis recurrence upon anti-PD-1 inhibitor rechallenge suggests a memory T cell-driven immune response. It also highlights that such irAEs were observed with the two PD-1 inhibitors pembrolizumab and tislelizumab used in this case and can be effectively managed. In this case, tumor progression was not observed after treatment cessation, although causality cannot be inferred.

Immune checkpoint inhibitor-induced bullous pemphigoid (ICI-BP) is a rare and complex cutaneous immune-related adverse event (cirAE) that often impacts the continuation of ICI therapy. Currently, there are no prospective clinical studies addressing the optimal management of BP alongside ICI continuation, with existing evidence largely derived from case reports or series. This study systematically analyzes published case reports and series to compile evidence regarding the management of ICI-BP and ICI rechallenge, aiming to inform clinical practice.

To identify the impact of CT-defined emphysema on efficacy and immune checkpoint inhibitor-related pneumonitis (ICIP) risk among non-small cell lung cancer (NSCLC) patients who receive ICIs.

Osteosarcoma is a primary bone malignancy of adolescents and young adults with marked heterogeneity and a high metastatic propensity. Five-year survival exceeds 70% in localized disease but falls to about 20% with pulmonary metastasis or chemoresistance, and overall outcomes have plateaued for decades. Extracellular vesicles (EVs) have emerged as critical mediators of osteosarcoma progression and metastasis. EVs remodel the tumor microenvironment (TME) by promoting immune evasion, extracellular matrix reprogramming, and angiogenesis, while also facilitating invasion, epithelial-mesenchymal transition (EMT)-like plasticity, and formation of lung pre-metastatic niches through organotropic integrins and glycoproteins. Their cargo, including proteins, lipids, and nucleic acids, drives intercellular communication that sustains proliferation, migration, and therapy resistance under metabolic or hypoxic stress. Clinically, the stability of EVs in body fluids and their tumor-specific molecular signatures highlight their promise as liquid-biopsy biomarkers for early diagnosis, prognosis, and treatment monitoring. Therapeutically, EVs are being engineered as delivery vehicles for drugs or RNA therapeutics, and interventions targeting their biogenesis, cargo sorting, or uptake are under exploration. Future research should integrate single-EV multi-omics, longitudinal cohort validation, and causal perturbation models to delineate functional mechanisms. Rational strategies that modulate EV dynamics and incorporate standardized analytic pipelines may transform EVs into actionable biomarkers and therapeutic targets, offering new avenues to overcome resistance and improve clinical outcomes in osteosarcoma.

The rapid advancements in nanotechnology have provided unprecedented opportunities for the clinical translation of vitamin C (VC) in cancer therapy. Although pharmacological doses of VC exhibit potent anti-tumor activities via multiple mechanisms-including selective pro-oxidative stress induction, metabolic inhibition, epigenetic modulation, and immune function enhancement-the clinical application of VC remains significantly hindered by its inherent instability, short biological half-life, and lack of tumor-specific targeting. Recent progress in the design and synthesis of VC and its derivatives combined with advanced nanocarriers has enabled precise delivery and efficient release of VC at tumor sites. In this review, we systematically summarize recent advances in nano-formulation strategies of VC, with a detailed discussion of lipid-based nanocarriers including liposomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), polymeric nanoparticles, as well as metal-based nanozyme delivery systems primarily composed of iron, copper, and manganese. These nano-systems not only significantly enhance the stability and circulation half-life of VC but also exploit tumor microenvironment-specific stimuli, such as pH, hydrogen peroxide (H2O2), and glutathione (GSH), to achieve responsive and precise drug release in cancer tissues. Notably, metal-based nanomaterials in combination with VC synergistically catalyze the Fenton reaction, markedly boosting reactive oxygen species (ROS) generation and demonstrating remarkable anti-tumor efficacy. Moreover, nanotechnology platforms have facilitated effective combination therapies involving VC with chemotherapeutic agents, photothermal catalysts, and immune agonists. Finally, this article highlights key challenges in the clinical translation of nano-formulated VC, including safety evaluation, scale-up production, and prediction of therapeutic efficacy. Future research directions in nano-drug design and exploration of synergistic mechanisms are proposed, providing theoretical guidance and practical insights for precise cancer therapy using VC-based nanomedicine.

Lung cancer is the malignant tumor with the highest incidence and lethality worldwide. Existing therapeutic modalities suffer from side effects, drug resistance, and limited efficacy, and there is an urgent need to develop safer and more effective therapeutic strategies. Curcumin (Cur) and astragaloside IV (AS) are promising natural anti-cancer agents. However, their poor aqueous solubility and low bioavailability limit their clinical efficacy. Natural cell membrane-based biomimetic drug delivery platform provides an effective strategy for efficient and targeted co-administration.

Chemotherapy, the first approach in breast cancer management, is limited owing to systemic toxicity and drug resistance. For instance, 5-fluorouracil in recommended doses cause severe side effects, highlighting the urgent necessity of finding more effective and safer combinations. Hence, this study aims to develop biocompatible natural-based nanocarriers for the co-delivery of loratadine, an antihistaminic drug along with 5-fluorouracil in order to enhance the anticancer efficacy while reducing the required dose of 5-fluorouracil.

The clinical advancement of cancer nanomedicine is significantly hindered by its limited accumulation in tumors, a key factor behind the frequent failure of nanodrugs in clinical trials. The effectiveness of these nanodrugs is closely tied to their route of administration, whether oral, transdermal, intravenous, or intracerebral, as each path presents unique physiological barriers that impede bioavailability and precise tumor targeting. Among the major causes of poor accumulation are rapid clearance by the mononuclear phagocyte system, opsonization accompanied by protein corona formation, renal filtration, and the abnormal, heterogeneous nature of tumor vasculature that restricts passive targeting via the enhanced permeability and retention (EPR) effect. In response, active targeting (AT) strategies have been widely explored, including surface modification with ligands, antibodies, or aptamers designed to bind specifically to overexpressed receptors on cancer cells or blood vessels. Despite these efforts, challenges such as the dense extracellular matrix, elevated interstitial fluid pressure, and the notable inconsistency of the EPR effect between animal models and human patients continue to limit therapeutic penetration. This review offers a systematic examination of nanodrug delivery pathways and the reasons behind their inadequate accumulation, highlighting the potential of both active targeting and combined passive-active strategies to enhance tumor-specific delivery. Overcoming these biological barriers through refined nano-design is crucial for developing the next generation of nanomedicines with improved tumor accumulation and treatment outcomes.

Colon cancer ranks as the third most common malignant tumor globally. Due to incomplete surgical resection and the multidrug resistance of tumor cells, it exhibits a high postoperative recurrence rate. Consequently, there is an urgent need to develop novel therapeutic strategies to inhibit postoperative recurrence of colon cancer.