Search Results (4,262)

Cellular senescence and polyploidy are fundamental stress responses that shape cancer progression and therapeutic outcomes. While senescence initially suppresses tumor growth, senescent cells accumulate in aging and therapy-exposed tissues and actively remodel the tumor microenvironment through the senescence-associated secretory phenotype (SASP) and extracellular matrix (ECM) reorganization. Senescent stromal cells increase collagen deposition and generate disordered matrix architectures, as evidenced by enhanced second harmonic generation (SHG) signal and increased anisotropic variation across in vitro systems, 3D co-culture models, and fibrotic lung tissues. These biochemical and mechanical alterations promote cancer cell plasticity and create conditions permissive for disease progression. Polyploid giant cancer cells (PGCCs) are a rare but highly resilient cancer cell population enriched under genotoxic stress. PGCCs arise through mitotic failure, including mitotic slippage and cytokinesis defects, and can survive chemotherapy and radiation due to their altered cell-cycle regulation. Emerging evidence indicates that senescence-driven microenvironments promote the formation of PGCCs and multinucleated cells, linking ECM remodeling and mechanical stress to polyploidization. Functionally, PGCCs exhibit abnormal cytoskeletal and nuclear mechanics that support migratory persistence and enable survival within hostile tumor environments. In addition, PGCCs can promote the survival of neighboring cancer cells during treatment, suggesting a stromal-like role in establishing therapy-resistant niches. These cells can persist in a dormant state and later generate proliferative progeny, contributing to tumor recurrence and metastasis. Together, these findings support a model in which senescent niches may promote PGCC formation, persistence, and tumor repopulation. Targeting both senescence-associated microenvironments and PGCC-specific survival mechanisms may improve long-term therapeutic outcomes. Full article

Triple-negative breast cancer is an aggressive and heterogeneous type of invasive breast cancer (BC) in which the cancer cells lack estrogen and progesterone receptors, as well as expression of the human epidermal growth factor 2 protein. This cancer tends to grow and spread faster than other BC subtypes, and is associated with a poor prognosis due to early visceral and neurological recurrences. Multidisciplinary management includes surgery, chemotherapy, radiation therapy, and immunotherapy with targeted immune checkpoint inhibitors (ICIs). The introduction of ICIs has improved outcomes in patients with TNBC, particularly in the metastatic and neoadjuvant settings. Despite these advances, a significant proportion of patients either do not respond to treatment or develop resistance to it. TNBC mortality remains high, underscoring the urgent need to identify novel prognostic and predictive biomarkers to overcome resistance to immunotherapy. Following a brief overview of the clinical features and established biomarkers of TNBC, the current review focuses on immune checkpoint proteins (ICPs) beyond PD-1 and PD-L1, and on the potential use of soluble ICPs rather than the well-established membrane-bound assays. These soluble ICPs are produced through the alternative splicing of messenger (m)RNA or the cleavage/shedding of membrane-bound proteins. This is followed by an overview of current treatment and novel predictive targets in TNBC. Additionally, the involvement of the B- and T-lymphocyte attenuator (BTLA)/herpes virus entry mediator (HVEM)/CD160 pathway and its role in the pathogenesis of BC and TNBC are reviewed, highlighting the potential use of BTLA and HVEM as biomarkers. Full article

Background: Gliomas are characterized by a high degree of molecular heterogeneity, which impairs the reproducibility of predictive biomarkers derived from bulk-based molecular profiling due to immune/stromal contamination of tumors and the high prevalence of the IDH mutation signature. Methods: In this study, we used MOFA+ to derive intrinsic molecular signatures from transcriptional, methylation, and genomic profiles of a cohort of 667 diffuse gliomas in the Cancer Genome Atlas database. Thereafter, factor scores were derived for two separate Chinese Glioma Genome Atlas batches (Batch 1, n = 325; Batch 2, n = 693) without any retraining on the model. The prognostic independence of identified molecular signatures was assessed using multivariable Cox regression adjusted for IDH mutation status and tumor purity; purity-residualized survival analyses; IDH-stratified Cox regression in each cohort; validation by concordance index against established molecular signatures; and survival extreme profiling. To characterize the biological significance of factor signatures, we projected gene set signatures corresponding to each factor signature onto a single-cell RNA-seq dataset of GBM (GSE131928). Results: MOFA+ identified 12 latent factors, of which a vascular–extracellular matrix (ECM) remodeling axis (Factor 1) explained the highest multi-omics variance (24.9%) and was the strongest independent prognostic factor. In multivariable Cox regression adjusting for IDH status and tumor purity, Factor 1 remained independently prognostic (HR = 1.67, 95% CI 1.27–2.20, p = 0.0002); in a fully-adjusted model additionally including age, WHO grade, MGMT methylation, and 1p/19q codeletion (plus radiotherapy and chemotherapy status in the CGGA cohorts), Factor 1 remained prognostic in both CGGA cohorts (CGGA1: HR = 1.50, p = 3.8 × 10⁻⁵; CGGA2: HR = 1.18, p = 0.003) but lost significance in TCGA (HR = 1.04, p = 0.83), consistent with the cohort-dependent magnitude reported in the IDH-stratified and meta-regression analyses below. Purity-residualized survival analysis showed negligible attenuation of the Factor 1 signal (raw HR = 3.57 vs. residualized HR = 3.72; concordance 96.5%). Within IDH-wildtype gliomas, Factor 1 was significant in both external validation cohorts (CGGA1: HR = 1.64, FDR = 4.6 × 10⁻⁶; CGGA2: HR = 1.20, FDR = 0.02), though the TCGA IDH-wildtype subgroup showed a trend that did not survive FDR correction (FDR = 0.060). All validation was performed without model retraining. Within IDH-mutant gliomas, Factor 1 was strongly prognostic in both CGGA cohorts but was not significant in TCGA (HR = 1.17, FDR = 0.33). These findings should therefore be interpreted as consistent in directionality across cohorts but not uniformly replicated at the FDR-adjusted significance threshold in the TCGA discovery dataset. Concordance index benchmarking on a matched subset (n = 503) showed Factor 1 achieved discrimination comparable to the Mesenchymal signature (C = 0.797 vs. 0.801; ΔC = −0.004) while outperforming four other established classifiers. Factor 1 consistently separated patients with extreme survival phenotypes (OS < 6 vs. >15 months) across all three cohorts (all log-rank p < 0.001). Projection onto a single-cell GBM atlas (GSE131928), supported by inferCNV-based malignant-cell classification, localized the Vascular–ECM program to malignant cells and the Immune–ECM axis to myeloid compartments. Conclusions: The Vascular–ECM axis is a consistent, prognostic program robust to purity adjustment for diffuse gliomas that remains relevant across IDH-defined subgroups in three independent datasets comprising 1685 patients. The Vascular–ECM axis is a reproducible, purity-robust prognostic program in diffuse glioma, with directionally consistent adverse effects across TCGA, CGGA Batch 1, and CGGA Batch 2 (pooled n = 1685). Given the strong co-loading of endothelial, ECM, and myeloid genes observed in the single-cell projection, Factor 1 is best interpreted as a vascular/ECM-associated tumor–microenvironment ecosystem program rather than a malignant-cell-autonomous signature. Its FDR-adjusted significance within IDH-stratified subgroups is cohort-dependent and robust in both CGGA cohorts but attenuated in the TCGA IDH-wildtype (FDR = 0.060) and TCGA IDH-mutant (FDR = 0.33) strata. The pooled signal should therefore be interpreted as evidence of a generalizable biological program rather than a uniformly replicated subgroup-specific biomarker. It is possible to calculate factor scores based on RNA sequencing alone using fixed loadings (Z = XWᵀ), which may have implications for future translational applications. All findings are correlative; a causal role for the Vascular–ECM program in glioma progression, invasion, or therapy resistance remains to be established through functional perturbation experiments. Full article

Background: Prostate cancer is a heterogeneous disease with variable clinical outcomes. If localized, the patient may be cured. However, prostate cancer is lethal if recurrence/progression to metastatic castrate resistant disease occurs. Thus, there is an unmet need to further understand the molecular underpinnings of this progression. Epidemiologic studies show that increased risk of developing and dying from prostate cancer has been associated with elevated serum IGF-1 levels, hyperinsulinemia and metabolic syndrome. Alterations in insulin pathway genes, such as PTEN, FOXO, and PIK3CA, are mutated in up to 32%, 15%, and 11% of localized prostate tumors, respectively. We aimed to further characterize expression of insulin pathway genes in localized prostate cancers in an effort to (1) provide insights into potential mechanisms of progression to metastatic disease and (2) try to further enrich for those prostate tumors that portend worse survival outcomes. Methods: Using the multi-institutional Oncology Research Information Exchange Network (ORIEN) database, gene expression data was analyzed from localized prostate cancer tumors. The raw counts were first normalized, and 176 genes related to the insulin receptor and its downstream pathways were then subset and used for clustering using the non-negative matrix factorization (NMF). The NMF cluster analysis was performed in an attempt to separate gene expression into two groups. Gene Set Enrichment Analysis (GSEA) was then performed between the two groups that had been separated by cluster analysis to determine homology between other GSEA sets. Kaplan–Meier curves were used to assess median overall survival. Cox analysis was performed to generate the adjusted KM curve. Mediation analysis was conducted to determine the relationship between cluster status, TN stage, and survival. Results: Cluster analysis revealed two distinct groups of insulin gene expression, cluster 1 (n = 96) and cluster 2 (n = 337). Compared with cluster 2, cluster 1 consisted of decreased expression of PTEN (p < 0.001) and PIK3R1 (p < 0.001), along with increases in the expression of AKT1 (p < 0.001), IRS1/2 (p < 0.001), FASN (p < 0.001), IGFBP2 (p < 0.001), and MTOR (p < 0.001). GSEA analysis revealed changes in lipid metabolism and WNT secretion pathways in cluster 1. Cluster 2 GSEA showed pathway changes related to DNA damage repair and testosterone. Patient characteristics between clusters differed significantly in the T and N stages of tumor but not in other ways. In unadjusted analysis, median overall survival was estimated at 117 months and 232 months for cluster 1 and cluster 2, respectively (p < 0.05). The proportion of patients who went on to develop metastases (p < 0.05) or need chemotherapy (p < 0.05) was increased in cluster 1 compared to cluster 2. Repeat survival analysis adjusted for confounders (T stage, N stage, age at diagnosis, pathologic grade) showed no difference in survival between clusters. Mediation analysis showed that the contribution of cluster status to survival was independent of T or N stage. Conclusions: A subset of localized prostate cancer patients demonstrated linked insulin pathway changes that are consistent with prior studies describing a pattern of insulin dysregulation. Though the group characterized by insulin dysregulation initially showed worse survival outcomes, this difference disappeared when controlling for confounders. Though baseline differences in tumor stage seemed to most readily explain the difference in survival between clusters, mediation analysis showed that the effect of cluster status on survival was independent of tumor stage. This suggests that other confounders, such as pathologic grade or baseline age, may explain the survival difference. Full article

The emerging threat of antibiotic-resistant pathogens and the limitations that conventional cancer chemotherapies display have created an urgent need for the development of innovative therapeutic strategies. Combining the pleiotropic biological roles of antimicrobial peptides (AMPs) and nanomaterials through their conjugation presents a promising possibility of targeting both microbial membranes and malignant cells. In the present study, we engineered a novel bioactive material by immobilizing the insect-derived AMP Papiliocin onto multi-walled—decorated with polyethylene–glycol—carbon nanotubes (PEG-MWCNTs) to prevent proteolytic degradation of the peptide and enhance its cellular delivery. Recombinant Papiliocin was cloned, heterologously expressed, purified and conjugated onto the PEG-MWCNT carrier. Successful expression and conjugation were validated via immunoblotting and Fourier transform infrared (FT-IR) spectroscopy, respectively. Further physicochemical characterization of the bionanocomposites was conducted using Dynamic Light Scattering (DLS) and Zeta potential measurements. Biologically, the biofunctionalized material exhibited potent, broad-spectrum antimicrobial activity both on Staphylococcus aureus and Escherichia coli, inhibiting almost 90% of the latter’s growth, highlighting the bioconjugate’s specific interactions with the Gram-negative pathogens’ membranes. Furthermore, it significantly reduced biofilm formation in Candida albicans, as indicated by the TCP assay. In parallel with its antimicrobial effects, CNTs-PEG–Papiliocin significantly reduced cancer cell viability and induced apoptosis via the extrinsic apoptosis pathway in HeLa cells, a response assisted by efficient intracellular delivery. Notably, cytotoxicity assays demonstrated lesser cytotoxic effect against non-tumorigenic HaCaT cells relative to the cancerous cell line. Collectively, these findings indicate the Papiliocin–biofunctionalized CNTs as a versatile, dual-action therapeutic agent with potential for antimicrobial activity and anticancer mode of action. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, with rising incidence and a 5-year survival rate of 13%. Late presentation, early metastasis, and intrinsic resistance constrain the efficacy of cytotoxic chemotherapy, which remains the backbone of PDAC treatment, with only modest survival gains and resistance nearly universal. Although KRAS mutations dominate tumour biology (~90% of cases), PDAC is a heterogeneous disease with distinct molecular subtypes that confer differential therapeutic vulnerabilities. Advances in comprehensive molecular profiling have catalysed a paradigm shift toward precision oncology in PDAC. In KRAS-mutant PDAC, mutation-specific inhibitors have established proof-of-concept, particularly in KRAS G12C disease, while next-generation approaches including KRAS G12D inhibitors, RAS-“ON” inhibitors, proteolysis-targeting chimeras (PROTACs), and KRAS-targeted vaccine strategies are expanding the therapeutic landscape. Combination strategies targeting upstream and downstream effectors of the RAS–MAPK pathway are also being explored to enhance the depth and durability of response. In parallel, KRAS-wild-type PDAC has emerged as a molecularly distinct subgroup enriched for rare but actionable alternative oncogenic fusion drivers including NRG1, NTRK, RET, ALK, and FGFR. Additional molecularly directed strategies targeting HER2 alterations, BRAF mutations, EGFR-dependent signalling, and tumour-selectively exposed surface antigens such as CLDN18.2 are under investigation across PDAC irrespective of KRAS mutation status. Synthetic lethal approaches, including targeting the PRMT5/CDKN2A/MTAP axis, represent a further emerging therapeutic strategy. Germline homologous recombination repair defects, particularly involving BRCA1/2 and PALB2, further define clinically important subsets with sensitivity to platinum chemotherapy and PARP inhibition. This review summarises current and emerging targeted and molecularly directed therapeutic strategies in PDAC, emphasising the importance of molecular stratification and recent advances shaping precision oncology in this historically treatment-refractory disease. Full article

Background: Platinum-based chemotherapy, including cisplatin and carboplatin, is widely used to treat various cancers, including ovarian cancer. However, its clinical application is limited by dose-limiting toxicities and resistance, with a poor 5-year overall survival rate for ovarian cancer (35–40%). In this study, we used ionisable lipids and developed pH-responsive lipid nanoparticles (LNPs) to address platinum-resistance in ovarian carcinoma. Methods: Cisplatin was loaded into three LNP systems containing monoolein (MO) and synthetic cationic ionisable lipids (OE-Mo, OA-Py, and OA-Pi) dispersed in Pluronic F-127 with 0.9% NaCl. Cisplatin-loaded LNPs (Cis-OE-Mo-NP, Cis-OA-Py-NP, and Cis-OA-Pi-NP) were characterised for size, zeta potential, and internal mesophase structure. Encapsulation efficiencies were determined via HPLC after removing free drug by ultrafiltration. In vivo efficacy was tested using cisplatin-resistant human patient-derived xenograft (PDX) models. Results: The LNPs were well dispersed with particle size of 219–250 nm and a drug loading of ~1.2 mg/mL. Encapsulation efficiencies were 62%, 59%, and 64%, for Cis-OE-Mo-NP, Cis-OA-Py-NP, and Cis-OA-Pi-NP, respectively. Small angle X-ray scattering (SAXS) results showed that the LNPs are pH responsive with structural transitions from a cubic to a hexagonal phase at an acidic pH. Among the tested formulations, Cis-OA-Py-NP resulted in the most significant reduction in tumour volume by ~60% compared to treatment with cisplatin alone. However, they also showed significant toxicity, including >10% weight loss and gross lung and kidney damage, as confirmed by histology. Conclusions: These findings highlight the potential of Cis-OA-Py-NP in reducing tumour volume but underscore the need for further optimisation to improve safety and therapeutic applicability. Full article

Protein lactylation, an emerging post-translational modification (PTM) driven by the metabolite lactate, has surfaced as an important regulatory layer contributing to the crosstalk between metabolic reprogramming and cellular functional plasticity in colorectal cancer (CRC). Within the unique “host–microbiota” symbiotic microenvironment of CRC, the Warburg effect—fueled jointly by oncogene activation and microbial metabolism—provides abundant substrates for lactylation. This modification is dynamically regulated by a complex enzymatic system comprising “Writers” (e.g., p300/CREB-binding protein [p300/CBP], alanyl-tRNA synthetase 1/2 [AARS1/2]) and “Erasers” (e.g., histone deacetylases [HDACs] and Sirtuins). Through intricate crosstalk with other PTMs, such as acetylation and ubiquitination, lactylation exerts critical regulatory effects on both the histone epigenetic landscape and non-histone protein functions. Functionally, lactylation not only drives malignant proliferation, invasion, and metastasis but also systematically remodels the immunosuppressive “cold” tumor microenvironment. Furthermore, it confers broad-spectrum resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy by orchestrating a ferroptosis defense network, enhancing DNA damage repair (DDR), and activating protective autophagy. This review systematically synthesizes the regulatory networks and biological functions of lactylation in CRC, deeply elucidating the core mechanisms underlying therapy resistance. Finally, we discuss the clinical translational potential of lactylation as a novel diagnostic/prognostic biomarker and therapeutic target, aiming to provide new theoretical foundations and strategic directions for overcoming current bottlenecks in CRC clinical treatment. Full article

Glioma, the most common and aggressive primary brain tumor, presents significant clinical management challenges due to difficulties in blood–brain barrier penetration, high tumor heterogeneity, and susceptibility to drug resistance and recurrence, leading to an extremely poor prognosis. Traditional Chinese Medicine (TCM), particularly its derived active ingredients and herbal formulations, with its advantages of multi-component, multi-target, and holistic regulation, demonstrates significant potential in the comprehensive treatment of this disease. This review systematically outlines the research progress in TCM for combating glioma. Regarding mechanisms of action, active TCM components not only directly inhibit tumors by inducing cell apoptosis but also exert synergistic therapeutic effects via multiple pathways. These include remodeling the immunosuppressive microenvironment, activating novel cell death programs such as ferroptosis and immunogenic cell death, intervening in tumor metabolic reprogramming, and reversing chemotherapy resistance. In terms of overcoming delivery barriers, drug delivery systems represented by nanocarriers, liposomes, and extracellular vesicles, combined with the penetration-enhancing effects of aromatic orifice-opening herbs (a class of TCM medicinals traditionally used to “open the orifices” and awaken the mind, now recognized to transiently enhance BBB permeability), have significantly improved the brain-targeting efficiency and bioavailability of TCM components. For clinical translation, a number of innovative drugs derived from TCM, such as elemene, cinobufagin, and ACT001, are currently under clinical investigation, with initial results showing efficacy in prolonging survival and improving quality of life. In the future, by integrating the analysis of multi-target synergistic mechanisms, promoting the clinical translation of intelligent drug delivery systems, and conducting high-quality clinical research on integrated Chinese and Western medicine, TCM is expected to provide a new generation of integrated treatment strategies for glioma that combines holistic and precision medicine. Full article

Chemotherapy-induced metabolic reprogramming of glioblastoma multiforme (GBM) cells increases intracellular levels of reductive and energetic carriers, thereby fueling drug-relocation and retention systems and enhancing GBM drug-resistance. We have previously shown the role of this process in the adaptation of poly(morpho)nuclear “giant” cells (PGCs) in T98G populations to doxorubicin (DOX)-induced stress. Here, we addressed the role of a “resistance triad”, which coordinates metabolic T98G reprogramming with the activation of the drug-relocation and drug-retention axis, in the recovery of GBM populations from chemotherapeutic stress. A combination of proteomic analyses with metabolic and phenotypic profiling of pulse DOX-treated T98G cells revealed the significance of mitochondrial dynamics for the efficiency of the T98G “resistance triad”. DOX-induced mobilization of ATP-generating systems and ATP-dependent anabolic pathways was accompanied by the formation of DOX-negative, “mosaic” mitochondrial networks and the upregulation of mitofusin-2 (MFN2) in T98G PGCs. Transient MFN2 down-regulation correlated with the respiratory capacity of T98G cells, while impairing cell welfare in the absence and presence of DOX. However, minute fractions of PGCs, which withstood combined MFN2 down-regulation and pulse DOX treatment, retained mitochondrial networks and displayed efficient ABC transporter-/V-type channel-dependent lysosomal DOX retention. Collectively, a “triad” of mitochondrial activation, ABC transporter-dependent perinuclear redistribution and V-type channel-mediated lysosomal DOX compartmentalization determines DOX resistance of T98G cells. Whereas MFN2-dependent mitochondrial rearrangements may contribute to these processes, complementary adaptative mechanisms can compensate MFN2 dysfunction, limiting its potential as a therapeutic target. Full article

Breast cancer is one of the most devastating malignancies in women worldwide. A growing body of evidence has linked neoplastic growth, invasion, metastasis, immune escape, and therapeutic resistance to infiltrating tumor-associated macrophages. In a breast cancer mass, macrophages are largely polarized to two main subtypes, M1 and M2, albeit with continuum intermediates, based on their immunological behaviors, gene signatures, and functional roles. While the former portrays proinflammatory and anti-cancer effects, the latter elicits the opposite impacts. M2 macrophages have gained rising attention as they are largely involved in fostering an immune-suppressive, cancer-promoting landscape and are imperative for malignant features across breast cancer subtypes. Through a positive feedback paracrine loop, M2 macrophages can be enriched by a plethora of dysregulated oncogenic signaling mediators, exemplified by CSF1/CSF1R, STAT3, IL-6, YAP, PI3K, PDK1, and AKT. These modulators could be released from or activated by surrounding malignant cells, fibroblasts, secreted extracellular vesicles, cell fragments generated after chemotherapies, hypoxia, dysregulated immune checkpoint pathways or oncometabolites. This review aims to discern the molecular cues fortifying M2 subpopulations. Moreover, recent advances in single-cell sequencing, spatial, and computational approaches have refined the understanding of TAM heterogeneity, while clinical translation remains limited by low therapeutic specificity, compensatory signaling, and differences between murine and human macrophage biology. Future therapeutic regimens should include strategies aimed at correcting aberrations that favor M2 polarization and are justified with divergences between humans and mice. Full article

Endometrial cancer (EC) is increasingly recognized as a heterogeneous disease, yet current treatment strategies often fail to explain why tumors with similar molecular profiles respond differently or develop resistance. This gap points to regulatory mechanisms beyond static genomic alterations. Epigenetic dysregulation through DNA methylation, histone modification, and non-coding RNA (ncRNAs) networks acts as a dynamic and reversible system that governs how tumors adapt under therapeutic pressure. In EC, alterations affecting key regulators such as MLH1, PTEN, and hormone receptors directly influence sensitivity to immunotherapy, targeted therapy, and endocrine treatment, defining treatment-responsive and treatment-resistant states. These observations shift the role of epigenetics from a descriptive feature of tumor biology to a determinant of therapeutic behaviour. Epigenetic states influence immune recognition, pathway activation, and cell cycle control, thereby shaping response to chemotherapy and immune checkpoint blockade. Biomarkers derived from these alterations, including methylation signatures and circulating RNAs, offer opportunities for patient stratification and longitudinal monitoring of treatment response. Therapeutically, targeting epigenetic regulators provides a strategy to reverse resistance and restore treatment sensitivity. DNA methyltransferase and histone deacetylase inhibitors, particularly in combination with established therapies, have shown potential to enhance treatment efficacy. Emerging approaches, including locus-specific epigenetic editing and liquid biopsy–guided monitoring, further support adaptive treatment strategies. Integrating epigenetic reprogramming into clinical decision-making offers a practical path toward improving treatment response and overcoming resistance in EC. Here, we propose an Epigenetic State–Response Framework (ESRF) in which dynamic epigenetic states define treatment-sensitive and resistant phenotypes, map to specific therapeutic vulnerabilities, and can be actively reprogrammed to restore treatment response. Full article

Background: South Korea continues to report a considerable burden of drug-resistant tuberculosis (TB). Bedaquiline-containing regimens are recommended for multidrug-resistant pulmonary TB, but evidence regarding the optimal treatment for extrapulmonary manifestations such as spinal TB remains limited. Case presentation: Herein, we report two cases of drug-resistant tuberculous spondylitis that were successfully managed using bedaquiline-containing regimens. Case 1 involved a 67-year-old man who was receiving chemotherapy for lymphoma and had a history of spinal TB treated 20 years earlier. The patient presented with dysphagia and upper limb weakness. Cervical magnetic resonance imaging revealed C4–5 spondylitis with an epidural abscess. He underwent surgical treatment, and Mycobacterium tuberculosis resistant to rifampin was isolated from cultured intraoperatively obtained tissue specimens. The patient received an antibiotic regimen consisting of bedaquiline, levofloxacin, linezolid, cycloserine, and clofazimine. Clinical and radiological improvements were achieved after 12 months of this treatment; bedaquiline was included in the regimen for the first 6 months, while the other agents were continued for the entire course. Case 2 involved a 71-year-old man with T12–L2 spondylitis and a left psoas abscess. Tissue culture confirmed Mycobacterium tuberculosis resistant to isoniazid, rifampin, and ethambutol. The patient was started on the same bedaquiline-containing regimen. Clinical and radiological improvements were observed after 18 months of this therapy, including 6 months of bedaquiline. Conclusions: Our clinical experiences suggest that bedaquiline-containing regimens represent a feasible and effective therapeutic option for drug-resistant tuberculous spondylitis. Larger studies are warranted to establish the optimal management strategies for extrapulmonary drug-resistant TB infections. Full article

Glioblastoma (GBM) remains the most aggressive primary malignant brain tumor in adults, with limited survival benefit from the current standard of care consisting of maximal safe resection, radiotherapy, and temozolomide-based chemotherapy. The highly infiltrative growth pattern, profound intratumoral heterogeneity, and strongly immunosuppressive tumor microenvironment together contribute to therapeutic resistance and frequent recurrence. In this context, oncolytic herpes simplex virus (oHSV) has emerged as a promising therapeutic platform for glioblastoma because of its dual capacity to directly lyse tumor cells and stimulate antitumor immune responses. In addition, the large viral genome and well-characterized biology of herpes simplex virus enable extensive genetic engineering to improve tumor selectivity, safety, and immunomodulatory function. In this review, we summarize the molecular design strategies that have driven the development of oHSV for glioblastoma, including attenuation of neurovirulence, enhancement of tumor-selective replication, and arming with immune-stimulatory transgenes. We further discuss the major biological barriers within the GBM tumor microenvironment that continue to limit therapeutic efficacy, with particular attention given to representative engineered oHSV platforms and the lessons learned from preclinical and early-phase clinical studies. A dedicated section examines these barriers in detail, including restricted intratumoral viral spread, antiviral innate immunity, and immunosuppressive myeloid cell dominance. We also review current efforts to improve outcomes through rational combination strategies with radiotherapy, immune checkpoint blockade, cytokine modulation, and other multimodal approaches. Although encouraging advances have been achieved, the clinical translation of oHSV therapy for glioblastoma still faces substantial challenges in patient selection, delivery optimization, response assessment, and treatment integration. A deeper understanding of virus–host–tumor interactions and more precise engineering of viral platforms may help unlock the full potential of oHSV-based therapy. Overall, oHSV represents one of the most compelling translational approaches in glioblastoma and provides a valuable framework for the development of mechanism-driven viro-immunotherapy in neuro-oncology. Full article

Background/Objectives: Metastatic breast cancer (MBC) remains a daunting clinical challenge, accounting for approximately 90% of all breast cancer-related deaths. The management of MBC has shifted from traditional chemotherapy to a sophisticated, biomarker-driven model of precision oncology. This evolution is predicated on the ability of biomarkers to provide prognostic and predictive information. The objective of this review is to provide a comprehensive synthesis of the current landscape of biomarker testing in MBC, detailing which biomarkers to test and the clinical rationale for doing so. Methods: This is a comprehensive review based on current international clinical practice guidelines, peer-reviewed literature, and evidence regarding clinically actionable and emerging biomarkers in metastatic breast cancer. Results: Key biomarkers currently in routine use include the established estrogen receptor (ER), progesterone receptor (PR), and HER2, alongside newer, clinically actionable alterations such as mutations in PIK3CA and ESR1, germline/somatic BRCA1/2, and PD-L1 expression. Furthermore, liquid biopsy, particularly the analysis of circulating tumor DNA (ctDNA), is rapidly gaining prominence as a non-invasive tool for real-time disease monitoring and resistance detection, highlighting the critical need for re-testing at metastasis due to tumor heterogeneity. Conclusions: The future of personalized oncology in MBC will be defined by the seamless integration of dynamic biomarkers and cutting-edge technologies. The integration of AI and spatial transcriptomics will move the field of pathology beyond a static diagnosis to a more dynamic and predictive model, reinforcing the pathologist’s role as the “molecular gatekeeper” for adaptive and personalized cancer care. Full article