Search Results (2,956)

Gastric cancer remains a leading cause of cancer-related mortality worldwide, largely due to resistance to platinum-based chemotherapy. Indoleamine 2,3-dioxygenase 1 (IDO1) has been implicated in tumor progression and immune evasion; however, its cell-intrinsic role in chemoresistance remains incompletely understood. This study demonstrates that IDO1 functions as a critical regulator of cisplatin sensitivity in gastric cancer cells through a ROS-mediated mechanism. IDO1 expression was suppressed using siRNA in two gastric cancer cell lines, AGS and MKN45, followed by cisplatin treatment. Cell viability, oxidative stress levels, apoptosis-related gene expression, and caspase-3/7 activity were assessed to evaluate the functional consequences of IDO1 knockdown. IDO1 silencing significantly enhanced cisplatin-induced cytotoxicity in both cell lines, accompanied by increased intracellular reactive oxygen species (ROS) levels and a marked transcriptional shift toward a pro-apoptotic gene expression profile characterized by upregulation of Bax and p53 and downregulation of anti-apoptotic Bcl-2. Critically, functional apoptosis analysis revealed that combined IDO1 silencing and cisplatin treatment markedly increased caspase-3/7 activity, confirming activation of the execution phase of apoptosis. These findings establish that IDO1 limits apoptotic susceptibility in a cell-intrinsic manner and contributes to cisplatin sensitivity in gastric cancer cells. The mechanistic basis involves IDO1’s ROS-scavenging function: by suppressing IDO1, cells lose their capacity to neutralize ROS, leading to excessive ROS accumulation that triggers mitochondrial dysfunction and activates p53-dependent apoptotic pathways. In conclusion, this study identifies IDO1 as a key regulator of oxidative stress-associated, caspase-dependent apoptosis in gastric cancer and suggests that targeting IDO1 in combination with platinum-based chemotherapy represents a promising strategy to enhance the efficacy of gastric cancer treatment. These findings provide a rationale for clinical translation and provide a foundation for future preclinical and clinical studies. Full article

Anti-CD38 monoclonal antibodies have substantially improved outcomes in multiple myeloma (MM). Although daratumumab and isatuximab target the same antigen, accumulating evidence indicates that they differ in epitope recognition, biological activity, and immunomodulatory properties, suggesting these agents may not be therapeutically interchangeable. This review summarizes the molecular and immunological mechanisms underlying their distinct antitumor effects and their implications for treatment selection. Isatuximab binds near the catalytic site of CD38, resulting in potent enzymatic inhibition, enhanced antibody internalization, FOXM1 suppression, and reactive oxygen species-mediated cytotoxicity, which may preferentially target MM cells harboring 1q21 amplification. In contrast, daratumumab exerts prominent Fc-dependent immune effects, including trogocytosis-mediated downregulation of CD38 and VLA-4, suppression of cell adhesion-mediated drug resistance, and modulation of the immune microenvironment, potentially enhancing subsequent T-cell-redirecting therapies. We further discuss the relevance of these mechanistic differences to measurable residual disease, extramedullary disease, and sequencing with BCMA- and GPRC5D-directed immunotherapies. Finally, we propose a biology-guided treatment-selection model integrating genomic alterations, tumor biology, and immune remodeling to support precision medicine for patients with MM. Full article

Podophyllotoxin (PPT) inhibits tumors such as lung cancer and breast cancer. However, it has poor water solubility and causes gastrointestinal dysfunction and bone marrow suppression, which severely limit its clinical application. Based on the differential reactive oxygen species (ROS) levels between tumor microenvironments and normal tissues, we designed and constructed a ROS-responsive micelle delivery system, successfully fabricating blank micelles (M) and PPT-loaded micelles (M@PPT). Both micelles exhibited good particle size uniformity, colloidal stability, and biosafety. The ROS responsiveness experiment revealed that, after incubating blank micelles (M) with 10 mM H₂O₂, the particle size increased significantly, and the size distribution broadened. High-performance liquid chromatography (HPLC) confirmed the release of cinnamaldehyde from the micelles upon H₂O₂ exposure. Additionally, DCFH-DA assays demonstrated that treatment with blank micelles (M) enhanced intracellular ROS levels. In vitro release studies showed that drug-loaded micelles (M@PPT) achieved 77.76% cumulative PPT release within 24 h in a buffer containing 10 mM H₂O₂, significantly exceeding the release observed in the H₂O₂-free control group. These results collectively validate the ROS-responsive disintegration of micelles and the subsequent release of cinnamaldehyde. The liberated cinnamaldehyde further amplified intracellular ROS levels, establishing a positive feedback loop that accelerated drug release. Cellular assays revealed superior tumor growth inhibition by M@PPT over free PPT, mediated through apoptosis induction, G2/M phase cell cycle arrest, downregulation of the anti-apoptotic protein Survivin, and upregulation of the p21 protein. In vivo studies further confirmed the enhanced antitumor efficacy and improved biosafety of M@PPT compared to free PPT. This ROS-responsive micellar system, by enabling tumor-targeted drug delivery and controlled release, provides a novel strategy to optimize the clinical utility of podophyllotoxin-based chemotherapeutics. Full article

Radiotherapy is a cornerstone of breast cancer treatment, but its efficacy is frequently limited by intrinsic and acquired radioresistance as well as dose-limiting toxicity to surrounding normal tissues. Nanoparticle-mediated radiosensitization has emerged as a promising strategy to enhance the therapeutic index of irradiation by combining physical dose amplification with biological, microenvironmental, and immunological modulation. In this systematic review, we evaluated preclinical evidence on nanoparticle-mediated radiosensitization in breast cancer, with emphasis on nanoplatform design, mechanistic patterns, therapeutic efficacy, and translational relevance. A total of 66 studies published between 2015 and 2026 were included. The identified systems encompassed a broad range of materials, including gold-, silver-, platinum-, bismuth-, gadolinium-, polymer-, lipid-, and hybrid-based nanoplatforms, frequently incorporating targeting ligands, catalytic components, biomimetic coatings, or therapeutic payloads. Enhanced radiation responses were most commonly associated with high-atomic-number (high-Z)-mediated energy deposition, increased reactive oxygen species generation, and enhanced DNA damage persistence. Additional mechanisms, including redox modulation, hypoxia targeting, regulated cell death, and immune activation, reflect the evolution of nanoparticle-assisted radiotherapy from predominantly physical radioenhancement toward multifunctional physicobiological strategies. Triple-negative breast cancer models predominated throughout the literature. Across preclinical models, nanoparticle-assisted irradiation consistently improved clonogenic survival, tumor control, and, in selected studies, survival. However, substantial heterogeneity in study design and limited use of rigorous radiobiological endpoints restricted cross-study comparability. The available preclinical evidence indicates that the most promising nanoparticle-mediated radiosensitization strategies integrate physical dose enhancement with biologically active mechanisms targeting oxidative stress, hypoxia, persistent DNA damage, immune signaling, and tumor microenvironmental resistance. Collectively, these findings suggest that the field is evolving from predominantly physical radioenhancement toward multifunctional, mechanism-driven physicobiological strategies. However, clinical translation remains constrained by methodological heterogeneity and limited radiobiological validation, highlighting the need for standardized preclinical evaluation and clinically feasible nanoplatforms tailored to subtype-specific mechanisms of radioresistance. Full article

Hypoxia and the evolving concept of pseudohypoxia are critical in driving tumor angiogenesis, contributing to malignancy progression and therapeutic resistance. Angiogenesis, a common feature of many solid tumors, is promoted by hypoxia-induced overexpression of pro-angiogenic factors (e.g., VEGF, FGF) and genetic mutations (e.g., VHL, SDH) that stabilize hypoxia-inducible factors (HIF) even in normal oxygen conditions, a phenomenon known as pseudohypoxia. Recent experimental studies challenge the view that hypoxia universally enhances vessel growth. In certain models, severe oxygen deprivation impairs angiogenesis. Furthermore, tumor-mediated metabolic reprogramming can drive immune evasion via HIF stabilization in immune cells. These paradoxes, together with persistent therapy resistance and the limited effectiveness of current anti-angiogenic treatments, reveal critical gaps in our understanding of how hypoxic signaling modulates vascular and immune dynamics within the tumor microenvironment. These complexities demand more detailed exploration of underlying processes and the development of innovative therapeutic strategies. Here, we review recent mechanistic studies on tumor angiogenesis, summarizing therapeutic and diagnostic advances from both preclinical and clinical studies. We further discuss strategies to exploit hypoxic vulnerabilities, including HIF inhibitors, hypoxia-activated prodrugs, vascular normalization, combination regimens to restore immunity, biomarker-guided patient selection, and advanced hypoxia-targeted imaging to improve outcomes in angiogenesis-driven cancers. Full article

Reactive oxygen species (ROS)-regulated antioxidant defense is closely linked to non-small cell lung cancer (NSCLC) progression and therapy resistance. Wogonin (WGN), a flavonoid from Scutellaria baicalensis, has antitumor activity, but whether it is associated with ROS-dependent ferroptotic and mitochondrial stress in NSCLC remains incompletely defined. A549 and BEAS-2B cells, male BALB/c nude mouse A549 xenografts, patient-derived NSCLC organoids, and public transcriptomic cohorts were analyzed using viability, colony formation, migration/invasion, DCFH-DA ROS, JC-1, Annexin V/PI, Fe²⁺ and lipid ROS probes, RT-qPCR, Western blotting, immunofluorescence, inhibitor rescue, and c-Myc gain- and loss-of-function assays. WGN suppressed A549 growth and motility with weaker effects on BEAS-2B cells. WGN markedly increased intracellular ROS, Fe²⁺ accumulation and lipid peroxidation, decreased mitochondrial membrane potential, promoted Caspase-related apoptosis, reduced c-Myc/GPX4 and SLC7A11, and increased ACSL4. N-acetylcysteine, Z-VAD-FMK and Ferrostatin-1 partially rescued WGN-induced injury. c-Myc overexpression partially restored GPX4 and reduced lipid ROS/Fe²⁺ accumulation, whereas c-Myc knockdown decreased GPX4. Xenografts and organoids reproduced tumor inhibition and selected redox-associated molecular changes. Collectively, WGN suppresses A549-associated NSCLC phenotypes in association with ROS accumulation, ferroptosis-related lipid injury, mitochondrial dysfunction-associated apoptosis, and c-Myc/GPX4 downregulation. Full article

Anthracyclines such as doxorubicin (DOX) remain central components of breast cancer (BC) chemotherapy, although their efficacy is frequently limited by drug resistance. Myoglobin (MB), an oxygen-binding heme protein expressed in breast tumors, has been implicated in the detoxification of DOX in cardiomyocytes, but its role in BC remains unclear. Using MB-expressing and MB-knockout (MBKO) MDA-MB-468 BC cells, we demonstrate that MB confers hypoxia-dependent resistance to DOX. Under hypoxia, MB-expressing cells exhibited reduced intracellular DOX-associated fluorescence, enhanced superoxide generation, and decreased sensitivity to DOX, findings consistent with altered redox cycling and oxidative processing of the drug. Re-expression of MB in MBKO cells restored resistance, whereas pharmacological modulation of MB function using carbon monoxide-releasing molecule-3 and tert-butoxycarbonyl-alanine reversed MB-dependent reductions in intracellular DOX accumulation. In contrast, aclarubicin, an anthracycline lacking the hydroquinone moiety required for efficient redox cycling, failed to reproduce MB-dependent effects. Analyses of four independent neoadjuvant BC cohorts further demonstrated that elevated MB expression was consistently associated with reduced probability of achieving pathological complete response following anthracycline-containing chemotherapy. Collectively, these findings identify MB as a previously unrecognized modulator of BC response to redox-active anthracyclines and support its potential utility as both a predictive biomarker and therapeutic target. Full article

Although neoadjuvant chemotherapy is widely used after osteosarcoma (OS) surgery, suboptimal chemotherapy accelerates OS recurrence, and postoperative bone repair remains challenging. Here, we report a selenium-loaded biomimetic calcium phosphate (Se@BioCaP) to provide a long-term therapeutic-dose release for postoperative OS treatment. Sodium selenite was incorporated into a biomimetic calcium phosphate (BioCaP) via a wet biomimetic mineralization protocol. The release kinetics of Se@BioCaP achieved a transition from non-Fickian transport to Fickian diffusion, delivering sustained cytotoxic concentrations under acidic, tumor-like conditions while maintaining biocompatibility with osteoblasts (OBs) under physiological conditions. The reduction in OS cell viability was associated with the disruption of redox homeostasis, including the downregulation of key antioxidant enzymes (SOD2 and GPx1), increased reactive oxygen species (ROS), and acidic vesicular organelle (AVO) formation. Notably, Se@BioCaP200 extracts maintained in vitro anticancer and pro-osteogenic activity at day 42, while antibacterial activity was maintained through day 42. These findings suggest that Se@BioCaP may be a promising candidate for postoperative OS management. Full article

Anthralin has a long history as a topical treatment for psoriasis, where it reduces keratinocyte hyper-proliferation and effectively clears plaques. While it lowers inflammatory markers in psoriatic skin, it paradoxically induces inflammation in healthy skin through reactive oxygen species (ROS) and related pathways. However, its precise mechanism of action remains incompletely understood. Interestingly, the once undesirable pro-inflammatory effect in healthy skin may now represent a valuable adjuvant property for transcutaneous immunization (TCI). In particular, combining anthralin with the TLR7 agonist imiquimod (IMQ) elicits strong cytotoxic T-cell responses in pre-clinical studies. When paired with antigenic peptides that can penetrate the skin, this immunization approach is especially promising in the context of cancer therapy, given the central role of cytotoxic T-cells in tumor rejection. However, current evidence is largely derived from mouse models, but its efficacy and safety in humans remain to be established. This review therefore examines whether anthralin can be repurposed as a cutaneous adjuvant for transcutaneous immunization, and which mechanistic and translational constraints must be overcome before human application. Full article

Objective: Current therapeutic regimens for pancreatic neuroendocrine neoplasms (pNENs) remain limited and fail to yield notable improvements in overall survival. Therefore, the development of novel agents is of paramount importance. Bruton’s tyrosine kinase inhibitors (BTKis) have demonstrated promising therapeutic potential in solid tumors; however, ibrutinib, a classic BTKi, exhibits unsatisfactory clinical efficacy against pNENs. In this study, we synthesized a novel pyrrolopyrimidine-based BTKi, QY21, and aimed to investigate its inhibitory effects on pNEN cell proliferation both in vitro and vivo and identify the core signaling pathways mediating its suppressive effects on pNENs. Methods: CCK-8, EdU, and colony formation assays were conducted to assess the effect of QY21 on pNENs in vitro. Transcriptome sequencing, quantitative real-time PCR, Western blotting, and flow cytometry were employed to explore the mechanisms. A xenograft tumor model in nude mice was established for in vivo validation. Results: QY21 significantly suppressed pNENs proliferation in vitro. Compared with the control and ibrutinib groups, QY21 exhibited stronger tumor growth inhibition in vivo. Histopathological analysis revealed a decreased Ki-67 index in the QY21 group, with no significant organ-toxic lesions observed. Transcriptome sequencing identified ATF3 as the core mediator responsible for the anti-proliferative effect of QY21. ATF3 was poorly expressed in pNENs, while QY21 markedly upregulated ATF3 expression. Mechanistically, QY21 induced ferroptosis by elevating ATF3 levels. The knockdown of ATF3 or administration of ferrostatin-1 significantly attenuated the anti-proliferative capacity of QY21, accompanied by reduced accumulation of reactive oxygen species and lipid peroxidation. Conclusions: This study demonstrates that the novel BTKi QY21 suppresses pNENs proliferation by triggering ATF3-mediated ferroptosis, providing a potential preclinical strategy for pNENs. Full article

Lung cancer is the most common malignant tumor worldwide in terms of both incidence and mortality, and the development of highly effective, low-toxicity therapeutic strategies remains an urgent clinical challenge. Here, we report that Salvianolic acid A (SAA), a natural compound extracted from Salvia miltiorrhiza Bunge, inhibits the proliferation of non-small cell lung cancer (NSCLC) cells and induces ferroptosis. Mechanistically, SAA acts as an SRC kinase inhibitor, blocking SRC autophosphorylation at Tyr416, thereby disrupting the SRC-YAP interaction and preventing YAP nuclear translocation. This leads to GPX4 downregulation and subsequently triggers ferroptosis, characterized by increased reactive oxygen species (ROS), Fe²⁺ accumulation, and lipid peroxidation. Overexpression of YAP abrogates the effects of SAA, while inhibiting SRC or YAP enhances its activity. SAA inhibits tumor growth and downregulates key effector molecules in vivo. In summary, this study reveals a novel mechanism by which SAA induces ferroptosis via the SRC/YAP/GPX4 axis, supporting its further development as a candidate therapeutic agent for NSCLC. Full article

Osteosarcoma, the most common primary malignant bone tumor in adolescents, faces treatment challenges due to metastasis and chemoresistance. This study developed a novel Au@Rh core–shell nanoparticle system functionalized with indocyanine green (ICG) to overcome hypoxia-limited photodynamic therapy (PDT). Au@Rh nanoparticles were synthesized via wet chemistry and characterized by UV-Vis spectroscopy, TEM, and cyclic voltammetry (CV). The system exhibited a core–shell morphology, well-defined crystalline planes, photothermal conversion and electrocatalytic activity. The Au@Rh nanoparticles (109 nm total size, 90 nm Au core, and 15 nm Rh shell) demonstrated dual functionality: the gold core provided photothermal conversion (a 7 °C temperature increase under NIR irradiation), while the rhodium shell exhibited pH-independent electrocatalytic activity for H₂O₂ decomposition, generating oxygen to alleviate tumor hypoxia. Crucially, the system showed excellent biocompatibility, with no significant cytotoxicity in both osteosarcoma (HOS) or normal osteoblast (hFOB) cells after 48 h of exposure. When activated by NIR irradiation (808 nm, 16.6 J/cm²), the complete Au@Rh-ICG system achieved selective 67% cytotoxicity in HOS cells versus only 30% in hFOB cells, demonstrating targeted therapeutic efficacy. These results position Au@Rh-ICG as a promising theranostic platform for osteosarcoma treatment, combining enhanced PDT with photothermal therapy while addressing tumor hypoxia. Full article

Although perioperative oxygen therapy is a routine component of general anesthesia, its early biological consequences remain incompletely understood. This prospective randomized study evaluated whether perioperative oxygen concentration influences early biomarker responses in adults undergoing elective laparoscopic lower abdominal surgery. Patients received either normoxia (FiO₂ 0.35) or hyperoxia (FiO₂ 0.80) under standardized anesthesia. Clear physiological separation between groups was confirmed by arterial blood gas analysis. The primary biomarker finding was that circulating surfactant protein-A (SP-A) increased significantly in the normoxia group, whereas no comparable increase was observed under hyperoxia. Syndecan-1 and sialic acid showed descriptively similar directional patterns; however, these secondary biomarker findings were interpreted as exploratory and were not robust after Holm correction. By contrast, tumor necrosis factor-alpha (TNF-α) levels were higher postoperatively in the hyperoxia group, while ischemia-modified albumin (IMA) and total protein did not differ significantly between groups. These findings suggest that perioperative hyperoxia was associated with different early circulating biomarker trajectories across pulmonary epithelial and glycocalyx-related domains, without establishing pulmonary or endothelial protection. Further studies are needed to determine whether these early mechanistic findings translate into clinically meaningful outcomes. Full article

Inflammation contributes to the rapid progression of high-grade gliomas, indicating that anti-inflammatory strategies targeting NF-κB signaling may offer therapeutic benefit. Cannabidiol (CBD) and celecoxib (CELE) are hydrophobic pharmacological agents whose formulation in lipid carriers may support their combined biological evaluation. In this proof-of-concept study, we investigated liposomal formulations containing CBD, CELE, or both compounds in U-87 MG high-grade glioma cells and in a subcutaneous xenograft model. We assessed cytotoxicity, apoptosis, oxidative stress, Nrf2-dependent responses, NF-κB-centered inflammatory networks, tumor cell invasive properties, and Wnt/β-catenin pathway activity. The nanoformulations induced reactive oxygen species generation by 1.8-fold, which was accompanied by Nrf2 activation. Cationic formulations loaded with the compounds produced more pronounced pro-apoptotic effects (up to 39%) than POPC liposomes, although both types reduced the nuclear translocation of the NF-κB p65 subunit. The CBD + CELE-containing formulation showed a trend toward reduced tumor progression in mice. It is important to note that the in vitro and in vivo nanoformulations were physicochemically related, but not identical, and the in vivo experiment should be interpreted as a preliminary assessment after intratumoral administration. Overall, cationic liposomes co-loaded with CBD + CELE represent a promising platform for further optimization aimed at coordinated modulation of inflammatory, oxidative, and proliferative pathways in glioma. However, additional studies, including tissue distribution, release kinetics, and efficacy in orthotopic glioma models, are needed to fully verify their translational potential. Full article

Photodynamic therapy (PDT) represents a highly promising modality for cancer treatment; however, its clinical success is significantly restricted by the hypoxic nature of the tumor microenvironment (TME). Hypoxia also upregulates hypoxia-inducible factor-1α (HIF-1α) expression, thereby exacerbating tumor malignancy. To tackle this challenge, we engineered a hypoxia-activatable supramolecular nanoplatform (GH@CyNPs) capable of dual hypoxia reversal and amplification of PDT efficacy. The nanoplatform was constructed via host–guest interactions between a water-soluble pillar[5]arene (WP5) and an azobenzene-linked cyanine/YC-1 conjugate (Cy-G), followed by the co-encapsulation of glucose oxidase (GOx) and catalase (CAT). Upon entering the cancer cells via endocytosis, the azobenzene linker is specifically cleaved by the hypoxic TME, facilitating payload release. Concurrently, the released GOx/CAT pair drives in situ cascade reactions to generate oxygen (O₂), while YC-1 effectively suppresses HIF-1α expression, thereby achieving synergistic alleviation of hypoxia. Under irradiation, the released cyanine acts as a potent photosensitizer, generating abundant reactive oxygen species (ROS) to kill cancer cells. Both in vitro and in vivo evaluations corroborated that GH@CyNPs exhibit preferential tumor accumulation, profound antitumor efficacy, and excellent biocompatibility. This study presents an innovative paradigm for overcoming TME hypoxia to optimize photodynamic oncotherapy. Full article