Search Results (641)

Gold nanoparticles offer a versatile platform for cancer theranostics because their high atomic number can enhance X-ray energy deposition, their plasmonic properties support photothermal and photoacoustic applications, and their surfaces allow drug loading and molecular targeting. However, therapeutic benefit remains heterogeneous because tumor uptake, intratumoral coverage, and subcellular localization determine whether deposited gold can be converted into biologically effective damage. Redox context further shapes this conversion by determining whether AuNP-triggered physical or catalytic events can overcome local buffering and propagate into durable injury. During radiotherapy, AuNPs increase local secondary electron release and ROS formation, which can intensify DNA damage when GSH-dependent peroxide detoxification, thioredoxin-related buffering, and KEAP1-NRF2-regulated antioxidant responses are insufficient to contain the redox burden. In catalytic systems, Au-containing nanozymes can convert endogenous H₂O₂ into highly reactive radicals and may simultaneously deplete glutathione, thereby amplifying mitochondrial dysfunction and lipid peroxidation. During photoactivation, plasmonic heating and photosensitizer coupling further reshape ROS generation in a time-dependent and location-dependent manner. On the diagnostic side, CT or spectral CT can quantify tumor gold burden and coverage, whereas ROS-responsive photoacoustic, SERS, or fluorescence probes can report treatment-related oxidants and verify whether redox activation has occurred within the tumor. Clinical translation will therefore depend on quantification-guided dosing, definition of spatial coverage and activation timing, standardized redox-response readouts, and long-term safety evaluation. Full article

Glioblastoma multiforme (GBM) remains the most aggressive and therapeutically intractable primary brain tumor, with many patients experiencing rapid relapse despite maximal surgical resection followed by standard chemoradiation. This persistent failure reflects the convergence of profound tumor-intrinsic genetic heterogeneity and a highly dynamic, spatially structured, and immunosuppressive tumor microenvironment (TME). Together, these forces create strong selective pressures that fuel tumor evolution, intratumoral diversity, phenotype plasticity, diffuse invasion, and robust resistance to therapy. The TME of GBM is orchestrated through a complex interplay between diverse cellular constituents, including tumor-associated macrophages, reactive astrocytes, endothelial cells, pericytes, and GBM stem cells, and non-cellular components such as extracellular matrix remodeling, hypoxia, metabolic and nutrient gradients, and spatially patterned cytokine and chemokine signaling networks. Additionally, heterogeneity in blood–brain barrier (BBB) and blood–tumor barrier (BTB) complicates drug delivery and immune surveillance, reinforcing therapeutic resistance and regional tumor adaptation. Conventional two-dimensional cell cultures and animal models fail to sufficiently capture these multiscale, patient-specific interactions, limiting their translational predictive power. In this narrative review, we synthesize recent advances in GBM organoid technologies as physiologically relevant, three-dimensional platforms that more faithfully recapitulate TME for driving tumor evolution and treatment resistance. We compare complementary organoid strategies, including patient-derived GBM organoids that preserve native cytoarchitecture, cerebral organoid co-culture systems that reconstruct tumor–brain interactions, and advanced platforms incorporating immune and vascular features such as air–liquid interface cultures, microglia-enriched systems, and BBB/BTB-integrated models. Finally, we highlight emerging innovations such as spatial transcriptomics, organoid-on-a-chip systems, live imaging coupled with lineage tracing, genome engineering, and artificial intelligence integration that collectively position GBM organoids at the forefront of precision neuro-oncology, reproducing TME, enabling dynamic mapping of tumor evolution, and accelerating patient-specific therapeutic discovery. Full article

Cancer stem cells (CSCs) are a distinct subpopulation within a tumor that play an important role in tumor initiation, metastasis, therapeutic resistance, and cancer relapse. Their persistence is strongly influenced by the tumor microenvironment (TME), which provides a range of biological signals that maintain stemness, promote immune evasion, and resistance to cancer treatment. Therefore, effective targeting of CSCs is essential to improve therapeutic efficacy. In this review, we summarize the key characteristics of CSCs and their niche within the TME, emphasizing their interactions with immune cells, stromal components, and secreted factors. We also discuss the major challenges in targeting CSCs, including immune evasion, metabolic constraints, and intratumoral heterogeneity. We further highlight current and emerging immunotherapeutic strategies targeting CSCs, including immune checkpoint inhibitors, cancer vaccines, monoclonal antibodies, nanobodies, bispecific antibodies, antibody-drug conjugates (ADCs), CAR-T and CAR-NK cell therapies, oncolytic viruses, as well as innovative approaches such as targeted protein degradation. Finally, we emphasize the importance of a combinatorial approach that integrates CSCs targeting with modulation of the TME. Together, these strategies may lead to more durable responses, enhance therapy efficacy and reduce the risk of tumor recurrence. Full article

TRAF3 (TNF Receptor Associated Factor 3) is a regulator of NF-κB signaling, acting mainly as an inhibitor of the alternative NF-κB pathway. While TRAF3 has a well-established role in immune function, mainly via B- and T-lymphocyte regulation, its roles in cancer remain unclear. Breast cancer is the most common malignancy in women and a neoplasm displaying high levels of intratumoral heterogeneity. Identifying and understanding key molecules at the interface of breast cancer cells and the immune system is crucial for advancing therapeutic strategies for breast cancer patients. Here, by employing publicly available breast cancer datasets, breast cancer cell lines stably expressing TRAF3, mass spectrometry analysis in combination with functional assays, co-culture systems, and signal pathway characterization, we sought to assess the specific role of TRAF3 in breast cancer cells and how TRAF3-expressing breast cancer cells affect their immune microenvironment. Our results indicate that TRAF3 protein overexpression inhibits colony formation through apoptosis regulation. Proteome analysis for TRAF3 interactors and over-representation analysis identified multiple protein complexes related to cell cycle, apoptosis, and immune responses. Furthermore, TRAF3-expressing breast cancer cells displayed reduced levels of PD-L1 and when co-cultured with PBMCs induced a pro-inflammatory profile with increased CD16-NK cells and higher levels of IFN-γ and TNF-α and lower IL-10 and Tregs in the culture. These findings further expand the role of TRAF3 in breast cancer, not only as a regulator of EMT and survival of cancer cells, but also as a modulator of the tumor-immune microenvironment. Full article

Background/Objective: Basal cell carcinoma (BCC) is the most common cutaneous malignancy, arising from epidermal basal cells or the outer root sheath of the pilosebaceous unit. Despite its generally indolent clinical behavior, BCC exhibits substantial histopathological heterogeneity, which may reflect underlying biological differences among its subtypes. This study aimed to evaluate the expression of Wnt/β-catenin pathway components and tumor-associated markers—including COX-2, Ki-67, tryptase, CD1a, and WNT3A—across different histopathological subtypes of BCC. Methods: This retrospective cross-sectional study included 100 formalin-fixed paraffin-embedded (FFPE) BCC specimens retrieved between January 2006 and September 2015. After the exclusion of three cases due to inadequate tissue quality, the tumors were classified into nodular (n = 60), infiltrative (n = 16), superficial (n = 9), and other subtypes (n = 12). The immunohistochemical expressions of COX-2, Ki-67, CD1a, intratumoral and peritumoral tryptase, β-catenin, and WNT3A were assessed and compared among the BCC subtypes. Results: No significant differences were observed among the BCC subtypes regarding age or sex distribution. The expression levels of COX-2, Ki-67, CD1a, and mast cell-associated markers (intratumoral and peritumoral tryptase) did not differ significantly among the groups (all p > 0.05). Conversely, β-catenin expression was significantly higher in the infiltrative subtype compared with the other histological variants (p = 0.001). WNT3A immunoexpression was uniformly negative across all evaluated cases. Conclusions: Most of the evaluated immunohistochemical markers did not differentiate among the BCC subtypes. However, the significantly increased β-catenin expression observed in the infiltrative subtype suggests a potential association with tumor growth patterns rather than serving as a specific discriminative marker, thereby highlighting the biological heterogeneity of BCC. Although WNT3A expression was uniformly negative in all cases, this finding should be interpreted cautiously and does not allow for definitive conclusions regarding its role in Wnt pathway activation. Overall, these results support the need for further investigation into the Wnt/β-catenin pathway heterogeneity in BCC. Full article

Objectives: To exploratorily evaluate the potential of baseline dedicated breast PET (D-PET) for noninvasive prediction of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in HER2-positive (HER2+) breast cancer, and to investigate a fusion strategy integrating conventional radiomics and deep learning features. Methods: We developed a multi-representation framework with radiomics based on data-driven high-/low-uptake metabolic subregions and deep learning trained on standardized 3D tumor volumes, and intratumoral heterogeneity (ITH) was quantified on the largest slice as an additional comparator. The outputs of these pathways were subsequently integrated through feature-level and decision-level fusion. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), and interpretability analyses were applied to identify image regions and features contributing to predictions. Results: In a HER2-positive breast cancer cohort (n = 147) with baseline D-PET, deep learning (3D ResNet, AUC = 0.79) and radiomics (logistic regression, AUC = 0.78) achieved comparable performance on the primary test set, whereas the ITH model showed limited value (AUC = 0.61). Fusion further improved discrimination on test set 1, with an AUC of 0.83 for decision-level fusion and 0.84 for feature-level fusion. On test set 2, decision-level fusion achieved the highest AUC (0.84), and feature-level fusion maintained stable performance (AUC = 0.80). Conclusions: In this exploratory study, baseline D-PET showed promising performance for noninvasive prediction of NAC response in HER2+ breast cancer. The fusion of deep learning and radiomics yielded improvements over single-representation models, highlighting the potential role of D-PET models as decision-support tools. 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

Tumor-agnostic therapies represent an evolving approach in oncology, shifting from conventional histology-based treatment models to strategies guided by molecular alterations. Regulatory approvals of therapies targeting tumors harboring genomic alterations such as NTRK and RET fusions, BRAF V600E mutation, and those with deficient mismatch repair (dMMR) and a high tumor mutational burden (TMB-H) have demonstrated clinical activity across multiple cancer types. However, responses to these therapies are not uniform across all tumors. This review examines the variability of clinical outcomes across different cancer histologies and the challenges associated with this tumor-agnostic treatment paradigm. Despite sharing the same molecular alterations, some malignancies, including pancreatic and colorectal cancers, demonstrate lower response rates due to tissue-specific resistance mechanisms such as bypass signaling pathways and co-occurring genomic alterations. We discuss how these biological differences influence treatment response and their implications for future drug development and clinical trial design. Addressing these biological and clinical complexities will be essential to optimize the use of tumor-agnostic therapies across diverse cancer types. Full article

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype associated with limited therapeutic options and poor clinical outcomes. The aim of this research is to assess the prevalence, intensity, and distribution of integrin αvβ6 expression in TNBC using immunohistochemistry and to evaluate its potential as a predictive biomarker for αvβ6-targeted radionuclide therapy and other αvβ6-targeted theranostic approaches. Immunohistochemical analysis of integrin αvβ6 was performed on formalin-fixed, paraffin- embedded tumor samples from 48 patients with histologically confirmed TNBC. Staining intensity and the proportion of positive tumor cells were assessed using a semi-quantitative scoring system, and expression patterns were analyzed with regard to cellular localization and intratumoral heterogeneity. Moderate to strong integrin αvβ6 expression was observed in 43.8% of cases, with strong expression (≥50% of tumor cells) present in 25%. Expression was predominantly membranous, with occasional cytoplasmic staining, and demonstrated marked inter- and intratumoral heterogeneity. Integrin αvβ6 is frequently expressed in TNBC and represents a promising biomarker for patient selection in αvβ6-targeted radionuclide imaging and therapy. These findings provide a strong biological rationale for the clinical translation of integrin-targeted radioligands and support the development of personalized radiotheranostic strategies in TNBC. Full article

Background/Objectives: Laryngeal squamous cell carcinoma exhibits marked heterogeneity in clinical behavior, which cannot be fully explained by conventional histopathological parameters alone. Increasing evidence highlights the pivotal role of the tumor immune microenvironment in modulating tumor progression and patient prognosis. Methods: The study group had 82 patients with laryngeal squamous cell carcinoma. A panel of immunohistochemical markers was chosen to identify and quantify key immune cell populations and immune-related components within the tumor immune microenvironment. Semiquantitative evaluation of immune infiltrates was conducted, with particular emphasis on their density and relative distribution across intratumoral and stromal compartments. Results: Based on the resulting immunophenotypic profiles, cases were categorized into three distinct immune patterns: an active immune type, defined by a prominent and dense inflammatory infiltrate; a mixed type, exhibiting intermediate and heterogeneous immune characteristics; and an immunosuppressive type, characterized by reduced effector immune cell infiltration and a predominance of immunoregulatory elements. Statistical analysis demonstrated significant correlations between these immune patterns and patient survival outcomes. Conclusions: The present study aimed to characterize the immune landscape of laryngeal squamous cell carcinoma using immunohistochemical markers and to evaluate its prognostic significance. Full article

Background/Objectives: Molecular tumor profiling has recently transformed oncologic care delivery, establishing precision medicine as an essential approach for defining cancer biology and revealing intratumoral heterogeneity. The growing accessibility of advanced nucleic acid sequencing technologies has created a demand for specialized expertise in interpreting comprehensive genomic profiling results. Academic institutions currently employ a strategy of conducting initial broad-spectrum genomic testing, followed by matching patients to investigational therapies targeting their specific genomic alterations. Consequently, molecular tumor boards (MTBs) have emerged predominantly within major cancer centers and academic medical institutions, providing the specialized knowledge necessary to translate precision oncology into routine clinical care. However, despite the substantial benefits of collaborative case review within tumor boards, clinicians frequently encounter multiple barriers to effective MTB implementation. Methods: this report examines these challenges performing an exploratory quantitative synthesis approach and explores implementation strategies and best practices derived from collective institutional experiences, with the goal of establishing a functional MTB at the local level and thereby expanding oncology patient access to cutting-edge therapeutic options. Full article

Background: Gliomas exhibit substantial intratumoral heterogeneity, which limits prognostic precision and therapeutic efficacy. Selenoproteins are key regulators of redox homeostasis, but their role in glioma progression remains insufficiently defined. This study aimed to characterize glioma cells with high selenoprotein activity and to determine their biological and clinical significance. Methods: We performed integrated multi-omic analyses combining bulk transcriptomic, single-cell transcriptomic, and spatial transcriptomic data to identify and characterize glioma cell states associated with elevated selenoprotein expression. Functional validation was conducted using SELENOS knockdown assays to evaluate effects on glioma proliferation, invasion, tumor growth, macrophage recruitment, CSF1 expression, and macrophage polarization. Results: We identified a malignant glioma cell state, termed SehighMali, characterized by elevated selenoprotein expression and distinct metabolic and immunological features. SehighMali cells showed enhanced oxidative phosphorylation, MYC-associated transcription, and DNA repair activity, and preferentially engaged in immunosuppressive crosstalk with myeloid cells through the CSF1–CSF1R axis. Spatial analyses demonstrated enrichment of SehighMali cells in tumor cores and close colocalization with immunosuppressive myeloid populations. Across bulk cohorts, higher SehighMali abundance was associated with aggressive molecular features, poor clinical outcomes, and a predicted temozolomide-resistant phenotype. SELENOS knockdown suppressed glioma proliferation, invasion, and tumor growth, reduced macrophage recruitment, decreased CSF1 expression, and promoted macrophage polarization toward a pro-inflammatory phenotype. Conclusions: These findings define a selenoprotein-driven malignant glioma state associated with immune evasion and therapeutic vulnerability. They further identify SELENOS as a potential therapeutic target and provide insight into how selenoprotein-related programs contribute to glioma progression. Full article

Glioblastoma (GBM) remains one of the most challenging forms of cancer to treat, despite that extensive molecular profiling is now available. Indeed, intratumoral cellular heterogeneity, receptor redundancy, and adaptive resistance through compensatory signaling limit the impact of targeted therapies. Moreover, immunotherapies also underperform: checkpoint blockade and vaccine strategies did not obtain consistent benefits in a low mutational burden, poorly immunogenic tumor microenvironment (TME) dominated by immunosuppressive myeloid cells. In this article, we provide evidence that tumor-associated macrophages (TAMs), a form of CNS resident microglia and infiltrating macrophage, derived from bone marrow, adopt a spatially and transcriptionally distinct, non-binary continuum, shaped by tumor-derived signals and niche constraints, allowing glioma cells to resist to immune and pharmaceutical therapeutics. Metabolic rewiring, including hypoxia-linked glycolytic pressure, lactate signaling, and lipid-associated programs, determine immunosuppressive outputs and restrict plasticity, while epigenetic imprinting (DNA methylation, histone modifications, and chromatin regulators) stabilizes these programs and limits access to inflammatory loci. We discuss how stem cell secretome, and extracellular vesicles (EVs) and their cargo may act as tunable autocrine/paracrine inputs that may bias microglial regulatory control. Finally, we highlight major translational confounders, including EV operational definitions, blood–brain barrier (BBB) permeability and regional exposure, inconsistent dosing units, mixed myeloid compartments, and manufacturing dependent variability. Therefore, an exposure-aware framework that integrates product identity, delivery evidence, state-sensitive potency assays, and functional endpoints would be highly desirable. Full article

Background: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality despite major advances in diagnostics and therapies. The prognosis remains poor, mostly due to late-stage presentation and molecular heterogeneity. Epidermal growth factor receptor (EGFR) mutations are common drivers of NSCLC. The development of EGFR tyrosine kinase inhibitors (TKIs) has significantly improved outcomes in patients with EGFR mutations. Variant allele frequency (VAF) is a quantitative genomic measure representing the proportion of sequencing reads harboring a given mutation. In NSCLC tissue, the EGFR mutation VAF reflects tumor clonality and intratumoral heterogeneity, and accumulating evidence suggests an association between EGFR VAF and response to EGFR-targeted TKIs. Methods: To address the limited synthesis of data on the relevance of EGFR mutation VAF in NSCLC, we conducted a narrative review of the literature using PubMed/MEDLINE and Embase databases and current clinical guidelines, synthesizing available evidence on EGFR VAF, including its biological, molecular, and therapeutic implications in EGFR-mutated disease. The review was structured in accordance with the SANRA (Scale for the Assessment of Narrative Review Articles) checklist. Results: EGFR VAF and on-treatment VAF dynamics are consistently associated with treatment response, progression-free survival, and overall survival in osimertinib-treated NSCLC. Baseline VAF enables risk stratification, early clearance kinetics predict durable benefit, and longitudinal VAF monitoring facilitates early detection of resistance. Importantly, the prognostic implications of VAF differ fundamentally between tissue-based and plasma-based measurements: high tissue VAF reflects clonal homogeneity and predicts favorable TKI response, whereas high plasma VAF indicates elevated tumor burden and is associated with inferior outcomes. In the second-line setting, the T790M/activating mutation ratio serves as a surrogate for resistance clonality and independently predicts osimertinib efficacy. Conclusions: EGFR VAF represents a promising dynamic molecular biomarker for treatment monitoring and precision decision-making in EGFR-mutated NSCLC. Full article