Search Results (118)

Background/Objectives: The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is characterized by an enriched stroma, hampering the effectiveness of therapy. This co-clinical study aimed to (1) provide insight into early post-treatment changes in the TME using multiparametric magnetic resonance imaging (mpMRI)-derived quantitative imaging biomarkers (QIBs) in a preclinical PDAC model treated with radiotherapy and correlate these QIBs with histology; (2) evaluate the feasibility of obtaining these QIBs in patients with PDAC using clinically approved mpMRI data acquisitions. Methods: Athymic mice (n = 12) at pre- and post-treatment as well as patients with PDAC (n = 11) at pre-treatment underwent mpMRI including diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) data acquisition sequences. DW and DCE data were analyzed using monoexponential and extended Tofts models, respectively. DeepLIIF quantified the total percentage (%) of tumor cells in hematoxylin and eosin (H&E)-stained tissues from athymic mice. Spearman correlation and Wilcoxon signed rank tests were performed for statistical analysis. Results: In the preclinical PDAC model, mean pre- and post-treatment ADC and K^trans values differed significantly (p < 0.01), changing by 20.50% and 20.41%, respectively, and the median total tumor cells quantified by DeepLIIF was 24% (range: 15–53%). Post-treatment ADC values and relative change in v_e (rΔv_e) showed a significant negative correlation with total tumor cells (ρ = −0.77, p < 0.014 for ADC and ρ = −0.77, p = 0.009 for rΔv_e). In patients with PDAC, pre-treatment mean ADC and K^trans values were 1.76 × 10⁻³ (mm²/s) and 0.24 (min⁻¹), respectively. Conclusions: QIBs in both preclinical and clinical settings underscore their potential for future co-clinical research to evaluate emerging drug combinations targeting both tumor and stroma. Full article

While research on high-incidence tumors such as breast, prostate, and lung cancer has led to significant increases in patient survival in recent years, this has not been the case for low-incidence tumors such as high-grade gliomas, the most common and lethal brain tumors, for which the last significant therapeutic advance dates back to 2005. The high infiltration capacity of these tumors into normal brain tissue essential for both vegetative and relational life, the tumor microenvironment, with poor immunological activity, the multiple resistance mechanisms, and the unattractiveness of research investments due to the limited number of patients have made, and continue to make, the path to achieving significant improvements in the survival of patients with high-grade gliomas long and arduous. The objective of this article is to update the slow but continuous radiotherapeutic progress for adult and pediatric high-grade gliomas to the second half of 2023. We analyzed the progress of preclinical and clinical research on both adult and pediatric high-grade gliomas, with a particular focus on improvements in radiotherapy. Interactions between non-radiant new therapies and radiotherapy were also covered. A literature search was conducted in PubMed using the terms (“glioma* and radio*”) and the time limit of 1 July 2023 to 31 December 2023. The inclusion and exclusion criteria for the review were relevance to advances in radiotherapy for high-grade gliomas in adults and children. Treating patients with advanced disease progression only, using “historical” data as controls, as well as repurposing drugs developed for purposes completely different from their intended use, were the major (but not the only) methods to assess risk of bias in the included studies. The effect measures used in the synthesis or presentation of the results were tabulated and/or displayed in figures. A total of 100 relevant references were reviewed. Advances in preclinical studies and in clinical radiotherapy treatment planning, innovative fractionation, use of radioisotopes/radiopharmaceuticals, radiosensitization procedures, and radiation-induced damage were focused on. While this analysis may be limited by the relatively short publication period, high-grade glioma research remains impacted, especially at the clinical level, by potential issues with trial design, such as treating patients with advanced disease progression, using “historical” data as controls, and repurposing drugs developed for completely different purposes than intended. Addressing these aspects of high-grade glioma research could improve its efficacy, which often remains low despite the associated costs. Full article

Glioblastoma (GBM) is one of the most common and aggressive primary malignant tumors of the central nervous system, accounting for about half of all gliomas in adults. Despite intensive research and advances in molecular biology, genomics, and modern neuroimaging techniques, the prognosis for patients with GBM remains extremely poor. Despite the implementation of multimodal treatment involving surgery, radiotherapy, and chemotherapy with temozolomide, the average survival time of patients is only about 15 months. This is primarily due to the complex biology of this cancer, which involves numerous genetic and epigenetic abnormalities, as well as a highly heterogeneous tumor structure and the presence of glioblastoma stem cells with self renewal capacity. Mutations and abnormalities in genes such as IDH-wt, EGFR, PTEN, TP53, TERT, and CDKN2A/B are crucial in the pathogenesis of GBM. In particular, IDH-wt status (wild-type isocitrate dehydrogenase) is one of the most important identification markers distinguishing GBM from other, more favorable gliomas with IDH mutations. Frequent EGFR amplifications and TERT gene promoter mutations lead to the deregulation of tumor cell proliferation and increased aggressiveness. In turn, the loss of function of suppressor genes such as PTEN or CDKN2A/B promotes uncontrolled cell growth and tumor progression. The immunosuppressive tumor microenvironment also plays an important role, promoting immune escape and weakening the effectiveness of systemic therapies, including immunotherapy. The aim of this review is to summarize the current state of knowledge on the epidemiology, classification, pathogenesis, diagnosis, and treatment of glioblastoma multiforme, as well as to discuss the impact of recent advances in molecular and imaging diagnostics on clinical decision-making. A comprehensive review of recent literature (2018–2025) was conducted, focusing on WHO CNS5 classification updates, novel biomarkers (IDH, TERT, MGMT, EGFR), and modern diagnostic techniques such as liquid biopsy, radiogenomics, and next-generation sequencing (NGS). The results of the review indicate that the introduction of integrated histo-molecular diagnostics in the WHO 2021 classification has significantly increased diagnostic precision, enabling better prognostic and therapeutic stratification of patients. Modern imaging techniques, such as advanced magnetic resonance imaging (MRI), positron emission tomography (PET), and radiomics and radiogenomics tools, allow for more precise assessment of tumor characteristics, prediction of response to therapy, and monitoring of disease progression. Contemporary molecular techniques, including DNA methylation profiling and NGS, enable in-depth genomic and epigenetic analysis, which translates into a more personalized approach to treatment. Despite the use of multimodal therapy, which is based on maximum safe tumor resection followed by radiotherapy and temozolomide chemotherapy, recurrence is almost inevitable. GBM shows a high degree of resistance to treatment, which results from the presence of stem cell subpopulations, dynamic clonal evolution, and the ability to adapt to unfavorable microenvironmental conditions. Promising preclinical and early clinical results show new therapeutic strategies, including immunotherapy (cancer vaccines, checkpoint inhibitors, CAR-T therapies), oncolytic virotherapy, and Tumor Treating Fields (TTF) technology. Although these methods show potential for prolonging survival, their clinical efficacy still needs to be confirmed in large studies. The role of artificial intelligence in the analysis of imaging and molecular data is also increasingly being emphasized, which may contribute to the development of more accurate predictive models and therapeutic decisions. Despite these advancements, GBM remains a major therapeutic challenge due to its high heterogeneity and treatment resistance. The integration of molecular diagnostics, artificial intelligence, and personalized therapeutic strategies that may enhance survival and quality of life for GBM patients. Full article

Background: Chemotherapy, targeted therapy and radiotherapy are the cornerstones of cancer treatment. However, therapeutic resistance—not only to these classic modalities but also to novel therapeutics like immune checkpoint inhibitors (ICIs) and antibody-drug conjugates—remains a major hurdle. Resistance significantly limits efficacy and increases recurrence rates. A deep understanding of the molecular mechanisms driving this resistance is critical for developing personalized therapeutic strategies and improving patient outcomes. Recent Advances: Patient-derived cancer organoids have emerged as a powerful preclinical platform that faithfully recapitulates the genetic, phenotypic, and histological characteristics of original tumors. Consequently, PDOs are being widely utilized to evaluate drug responses, investigate resistance mechanisms, and discover novel therapeutic targets for a range of therapies. Limitations: While organoid models have been instrumental in studying resistance, significant limitations persist. First, standard organoid-only models lack key tumor microenvironment components, such as immune cells, limiting immunotherapy research. Second, there is a significant lack of research on acquired resistance, particularly in lung cancer. This gap is largely driven by the clinical infeasibility of rebiopsy in patients with progressive diseases. Third, the absence of standardized protocols for generating and validating resistance models hinders reproducibility and complicates clinical translation. Conclusions: This review summarizes recent advances in using organoid models to study resistance to chemotherapy, radiotherapy, and novel therapeutics (ICIs and ADCs). We emphasize the critical need for standardization in resistance organoid research. We also propose future directions to overcome existing challenges, including the integration of co-culture systems (to include the TME) and advanced technologies (e.g., scRNA-seq, Spatial Transcriptomics). Our specific focus is on advancing lung cancer resistance modeling to enable functional precision medicine. Full article

Background/Objectives: There is growing interest in the gut microbiome’s role in cancer, particularly its influence on prostate cancer therapy. This review explores how the gut microbiota modulates treatment outcomes and how prostate cancer therapies affect microbial composition. Methods: A semi-systematic PubMed search was performed for English-language articles published between 2010 and 2025 using relevant keywords related to prostate cancer therapy and the gut microbiome. Both original research and reviews were included, with additional studies identified through citation tracking. Results: The literature reveals a dynamic, bidirectional relationship between the gut microbiome and prostate cancer therapies. Gut microbes can modulate treatment efficacy and toxicity through immune regulation, metabolic activity, and the production of bioactive compounds such as short-chain fatty acids and tryptophan derivatives. These interactions influence responses to androgen deprivation therapy, chemotherapy, radiotherapy, and immunotherapy. In parallel, prostate cancer treatments induce notable shifts in gut microbial composition, reducing diversity, increasing intestinal permeability, and promoting dysbiosis. These changes may impair therapeutic outcomes. Specific microbial taxa, including Akkermansia muciniphila, Faecalibacterium, and Bacteroides, have been linked to both therapeutic response and microbiome alterations. Conclusions: The reciprocal influence between gut microbes and prostate cancer therapies presents a compelling avenue for therapeutic innovation. However, current knowledge is largely derived from preclinical or cross-cancer studies, highlighting a major evidence gap in prostate-specific research. Bridging this gap through well-designed translational studies could inform clinical strategies that harness microbiome modulation to enhance treatment efficacy, reduce toxicity, and personalize prostate cancer therapy. Full article

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Since the identification of dihydroorotate dehydrogenase (DHODH) as a mitochondrial suppressor of ferroptosis in 2021, increasing evidence has highlighted its role in linking nucleotide metabolism, redox regulation, and tumor progression. We conducted a comprehensive review of publications on DHODH, ferroptosis, and cancer. Relevant studies were analyzed to synthesize mechanistic insights, translational implications, and therapeutic perspectives. DHODH, a flavin-dependent mitochondrial enzyme catalyzing the oxidation of dihydroorotate to orotate, integrates pyrimidine biosynthesis with electron transport chain activity. Beyond its canonical metabolic role, DHODH regenerates ubiquinol (CoQ₁₀H₂) to suppress mitochondrial lipid peroxidation and ferroptosis. Elevated DHODH expression in colorectal, hepatocellular, breast, renal, and brain cancers correlates with poor prognosis, therapy resistance, and immune evasion. Pharmacological inhibition of DHODH disrupts pyrimidine synthesis and redox defense, sensitizing GPX4-low tumors to ferroptosis. Preclinical studies demonstrate synergy between DHODH inhibitors and chemotherapy, radiotherapy, or immune checkpoint blockade. Nanoparticle-based delivery systems enhance therapeutic efficacy by simultaneously targeting multiple ferroptosis defense arms while reducing toxicity. DHODH serves as both a metabolic and redox checkpoint in cancer, linking ferroptosis suppression to proliferation and immune escape. Targeting DHODH offers a promising strategy to dismantle cancer resilience, particularly in combination with ferroptosis inducers and immunotherapies. Future research should focus on biomarker-guided stratification, nanomedicine platforms, and clinical translation of DHODH inhibitors. Full article

Background: FLASH radiotherapy delivers ultra-high dose rates with normal tissue sparing, but mechanisms remain unclear. We present a streamlined workflow for establishing a LINAC-based electron FLASH (eFLASH) platform in low-resource settings without requiring vendor-proprietary hardware or software, or vendor-assisted modifications to broaden accessibility for FLASH studies. Methods: A LINAC was converted to eFLASH with pulse control and monitoring. Automatic frequency control (AFC) was optimized to stabilize dose per pulse (DPP). Beam data were measured with EBT-XD films, and a Monte Carlo (MC) model was commissioned for in vivo dose calculation. We demonstrated in vivo dosimetry in planning studies of mouse whole-brain and rat spinal cord (C1–T2) irradiation. We further assessed the impact of AFC optimization on the FLASH spinal cord study. Results: AFC optimization stabilized DPP at ~0.6 Gy/pulse, reducing large fluctuations under the default setting. MC agreed with measurements within 2% for PDDs and profiles. MC planning showed uniform whole-brain irradiation with 6 MeV FLASH, while the spinal cord study exhibited up to 10% dose fall-off within 1 cm along the cord, suggesting potential dose-volume effects confounding FLASH sparing. Following AFC optimization, 50% of the C1–T2 cord reached >133 Gy/s, a 23% increase versus default. Conclusions: We demonstrated a cost-effective eFLASH platform and verified its accuracy for preclinical studies, expanding the accessibility of FLASH research. Full article

Cancer continues to pose a major global health burden, with conventional therapeutic modalities such as surgical resection, chemotherapy, radiotherapy, and immunotherapy often hindered by limited tumor specificity, substantial systemic toxicity, and the emergence of multidrug resistance. The rapid advancement of nanotechnology has introduced functionalized nanomaterials as innovative tools in the realm of precision oncology. These nanoplatforms possess desirable physicochemical properties, including tunable particle size, favorable biocompatibility, and programmable surface chemistry, which collectively enable enhanced tumor targeting and reduced off-target effects. This review systematically examines recent developments in the application of nanomaterials for cancer therapy, with a focus on several representative nanocarrier systems. These include lipid-based formulations, synthetic polymeric nanoparticles, inorganic nanostructures composed of metallic or non-metallic elements, and carbon-based nanomaterials. In addition, the article outlines key strategies for functionalization, such as ligand-mediated targeting, stimulus-responsive drug release mechanisms, and biomimetic surface engineering to improve in vivo stability and immune evasion. These multifunctional nanocarriers have demonstrated significant potential across a range of therapeutic applications, including targeted drug delivery, photothermal therapy, photodynamic therapy, and cancer immunotherapy. When integrated into combinatorial treatment regimens, they have exhibited synergistic therapeutic effects, contributing to improved efficacy by overcoming tumor heterogeneity and resistance mechanisms. A growing body of preclinical evidence supports their ability to suppress tumor progression, minimize systemic toxicity, and enhance antitumor immune responses. This review further explores the design principles of multifunctional nanoplatforms and their comprehensive application in combination therapies, highlighting their preclinical efficacy. In addition, it critically examines major challenges impeding the clinical translation of nanomedicine. By identifying these obstacles, the review provides a valuable roadmap to guide future research and development. Overall, this work serves as an important reference for researchers, clinicians, and regulatory bodies aiming to advance the safe, effective, and personalized application of nanotechnology in cancer treatment. Full article

Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a pivotal vulnerability in oral squamous cell carcinoma (OSCC). This review provides an overview of ferroptosis mechanisms and their implications for OSCC pathobiology and therapy. OSCC cells exhibit heightened reliance on anti-ferroptotic defenses such as GPX4, SLC7A11, FSP1, and Nrf2, and disrupting these pathways suppresses tumor growth and restores sensitivity to chemotherapy, radiotherapy, and immunotherapy. Genetic and epigenetic regulators, including p53, PER1, circ_0000140, and STARD4-AS1, critically modulate ferroptotic sensitivity, while metabolic enzymes such as ACSL4, LPCAT3, and TPI1 link ferroptosis to cellular plasticity and resistance. Preclinical studies highlight the promise of small-molecule inhibitors, repurposed agents (e.g., sorafenib, artesunate, trifluoperazine), natural compounds (e.g., piperlongumine, Evodia lepta, quercetin), and nanomedicine platforms for targeted ferroptosis induction. We further address ferroptosis within the tumor microenvironment, highlighting its immunogenic and context-dependent dual roles, and summarize genomic and transcriptomic evidence linking ferroptosis-related genes to patient prognosis. Beyond cancer, ferroptosis also contributes to non-malignant oral diseases, including pulpitis, periodontitis, and infection-associated inflammation, where inhibitors may protect tissues. Despite these advances, clinical translation is constrained by the lack of safe ferroptosis inducers and validated biomarkers. Future research should focus on developing pharmacologically viable GPX4 inhibitors, refining biomarker-driven patient stratification, and designing multimodal regimens that combine ferroptosis induction with standard therapies while preserving immune and tissue integrity. Ferroptosis therefore represents both a mechanistic framework and a translational opportunity to reshape oral oncology and broader oral disease management. Full article

Very-high-energy electron (VHEE) beams, ranging from 50 to 300 or 400 MeV, are the subject of intense research investigation, with considerable interest concerning applications in radiation therapy due to their accurate energy deposition into large and deep-seated tissues, sharp beam edges, high sparing properties, and minimal radiation effects on normal tissues. The very-high-energy electron beam, which ranges from 50 to 400 MeV, and Ultra-High-Energy Electron beams up to 1–2 GeV, are considered extremely effective for human tumor therapy while avoiding the spatial requirements and cost of proton and heavy ion facilities. Many research laboratories have developed advanced testing infrastructures with VHEE beams in Europe, the USA, Japan, and other countries. These facilities aim to accelerate the transition to clinical application, following extensive simulations for beam transport that support preclinical trials and imminent clinical deployment. However, the clinical implementation of VHEE for FLASH radiation therapy requires advances in several areas, including the development of compact, stable, and efficient accelerators; the definition of sophisticated treatment plans; and the establishment of clinically validated protocols. In addition, the perspective of VHEE for accessing ultra-high dose rate (UHDR) dosimetry presents a promising procedure for the practical integration of FLASH radiotherapy for deep tumors, enhancing normal tissue sparing while maintaining the inherent dosimetry advantages. However, it has been proven that a strong effort is necessary to improve the main operational accelerator conditions, ensuring a stable beam over time and across space, as well as compact infrastructure to support the clinical implementation of VHEE for FLASH cancer treatment. VHEE-accessing ultra-high dose rate (UHDR) perspective dosimetry is integrated with FLASH radiotherapy and well-prepared cancer treatment tools that provide an advantage in modern oncology regimes. This study explores technological progress and the evolution of electron accelerator beam energy technology, as simulated by the ASTRA code, for developing VHEE and UHEE beams aimed at medical applications. FLUKA code simulations of electron beam provide dose distribution plots and the range for various energies inside the phantom of PMMA. Full article

Pre-clinical animal studies evaluating the ‘flash effect’ caused by ultra-high dose rate (≥40 Gy/s) favorably spares normal tissue from radiation-caused toxicity while maintaining anti-tumor effects like conventional (CONV) radiation. The goal of this study is to leverage an immune response resulting from the treatment combination of flash radiotherapy (Flash-RT) and LIFE (liquid immunogenic fiducial eluter) biomaterial incorporating an anti-mouse CD40 monoclonal antibody to enhance the therapeutic ratio in pancreatic cancer. Methods: A small animal FLASH radiation research platform (FLASH-SARRP) was utilized to deliver both ultra-high and CONV dose-rate irradiation to treat syngeneic subcutaneous pancreatic tumors generated in 8–10-week-old male and female C57BL6 mice. The efficacy of FLASH versus CONV radiotherapy (RT) at varying doses of 5, 8, 10, and 15 Gy delivered in a single fraction was evaluated by assessing tumor growth and mice survival over time or comparing tumor weight at 10 days post-treatment. Results: Similar tumor control capability was observed by the high-dose rate and conventional RT related to the control group. Nevertheless, longer survival was observed for the FLASH group at 5 Gy compared to CONV and control at either 5 Gy, 10 Gy, or 15 Gy doses. Multiplex immunofluorescence and immunohistochemistry results showed higher T-cell infiltration within the combination of RT (either FLASH or CONV) and LIFE biomaterial-treated tumors compared to the control cohort. Conclusions: This animal study serves as an impetus for future studies leveraging the immune response using the combination of FLASH and LIFE Biomaterial to enhance the efficacy of pancreatic cancer treatment. Full article

Ependymomas are a heterogeneous group of central nervous system tumors originating from ependymal cells, exhibiting significant variability in clinical behavior, prognosis, and treatment response based on anatomical location and molecular profile. Historically, diagnosis and grading relied on histopathological features, often failing to predict outcomes accurately across tumor subtypes. With the integration of molecular and epigenetic profiling, the classification and management of ependymomas have undergone a significant transformation, culminating in the updated 2021 World Health Organization Classification of Tumors of the Central Nervous System. This molecularly driven system emphasizes the relevance of DNA methylation patterns and fusion oncogenes, offering a more biologically accurate stratification of disease. These insights enhanced diagnostic accuracy and informed prognostic assessments, paving the way for new targeted therapies. Although conventional treatment primarily consists of surgical resection and radiotherapy, emerging preclinical and early-phase clinical studies suggest a potential for molecularly guided interventions targeting specific oncogenic pathways. Despite these advances, effective targeted therapies remain limited, highlighting the need for further research and molecular stratification in clinical trial design. Additionally, the practical implementation of molecular diagnostics in standard-of-care settings is challenged by cost, accessibility, and institutional variability, which may impede equitable integration. This review summarizes the evolution of ependymoma classification, current molecular subtypes, gaps in clinical application and their implications for personalized therapy and future clinical research. Full article

This review aims to point out the main achievements in the cutting-edge field of aptamer nanotechnology and its applications in the most frequent neuro-oncological and neurodegenerative diseases. The article discusses the properties, advantages and drawbacks of aptamers (AP), and their design and selection by various SELEX methods, as well as the synergical advantages as theranostics of the aptamer-functionalized nanoparticles (Ap-NP). The Ap-nanoconjugates properties are compared to those of Ap and unconjugated NP. Moreover, the article comparatively analyzes the aptamer-based approaches vs. antibody-drug conjugates vs. exosome-based delivery systems vs. unconjugated NP, as targeted therapies in neurodegenerative diseases and gliomas. The review presents major challenges in Ap-NP conjugates’ clinical progress (concerning the in vivo enzymatic stability, blood–brain barrier (BBB) permeability, selective intracellular uptake in the brain parenchyma and target tissues, rapid renal clearance, off-target toxicity, immunogenicity, reproductible manufacturing) and the investigated developmental strategies to solve them. Furthermore, relevant examples and comparative insights regarding preclinically tested Ap and Ap-NP conjugates are presented for targeted delivery systems loaded with chemotherapeutical drugs or genes, Ap-siRNA chimeras and immunotherapeutical aptamers, which are evaluated in glioblastomas (GBM), amyloidogenic diseases and multiple sclerosis (MS); radiotherapy enhancers in GBM; aptasensors for diagnostic and bioimaging-guided therapy in GBM, MS and amyloidopathies. The review finally points out future research directions in order to accelerate the clinical translation and the real-world impact as theranostics of the most preclinically advanced Ap-NP conjugates in major neuro-oncological and neurodegenerative disorders. Full article

Chimeric antigen receptor (CAR)-T-cell therapy has revolutionised haematological cancer treatment. However, its application in solid tumours remains significantly limited by the immunosuppressive tumour microenvironment (TME), poor antigen specificity, and physical barriers to infiltration. This review explores a compelling question: can CAR-T cells be adapted to overcome immunosuppression in solid tumours effectively? We provide an in-depth analysis of the immunological, metabolic, and structural challenges posed by the TME and critically evaluate emerging engineering strategies designed to enhance CAR-T cells’ persistence, targeting, and function. These include metabolic reprogramming, hypoxia-responsive constructs, checkpoint-resistant designs, and innovative delivery techniques such as locoregional administration and nanotechnology-assisted targeting. We highlight promising preclinical and early clinical studies demonstrating that armoured CAR-T cells secreting cytokines like interleukin (IL)-12 and IL-18 can reprogram the TME, restoring antitumour immunity. Moreover, we examine synergistic combination therapies that integrate CAR-T cells with immune checkpoint inhibitors, radiotherapy, oncolytic viruses, and epigenetic modulators. Special attention is given to personalised strategies, such as bispecific targeting and precision delivery to tumour-associated vasculature or stromal elements, which are showing encouraging results in overcoming resistance mechanisms. This review aims not only to synthesise current advancements but also to ignite optimism in the potential of CAR-T-cell therapy to breach the immunological fortress of solid tumours. As we enter a new era of synthetic immunology, this evolving landscape offers hope for durable remissions and novel treatment paradigms. For clinicians, researchers, and biotech innovators, this paper provides a roadmap toward transforming a therapeutic dream into clinical reality. Full article

Melittin, a cytolytic peptide derived from honeybee venom, has demonstrated potent anticancer activity through mechanisms such as membrane disruption, apoptosis induction, and modulation of key signaling pathways. Melittin exerts its anticancer activity by interacting with key molecular targets, including downregulation of the PI3K/Akt and NF-κB signaling pathways, and by inducing mitochondrial apoptosis through reactive oxygen species generation and cytochrome c release. However, its clinical application is hindered by its systemic and hemolytic toxicity, rapid degradation in plasma, poor pharmacokinetics, and immunogenicity, necessitating the development of targeted delivery strategies to enable safe and effective treatment. Nanoparticle-based delivery systems have emerged as a promising strategy for overcoming these challenges, offering improved tumor targeting, reduced off-target effects, and enhanced stability. This review provides a comprehensive overview of the mechanisms through which melittin exerts its anticancer effects and evaluates the development of various melittin-loaded nanocarriers, including liposomes, polymeric nanoparticles, dendrimers, micelles, and inorganic systems. It also summarizes the preclinical evidence for melittin nanotherapy across a wide range of cancer types, highlighting both its cytotoxic and immunomodulatory effects. The potential of melittin nanoparticles to overcome multidrug resistance and synergize with chemotherapy, immunotherapy, photothermal therapy, and radiotherapy is discussed. Despite promising in vitro and in vivo findings, its clinical translation remains limited. Key barriers include toxicity, manufacturing scalability, regulatory approval, and the need for more extensive in vivo validation. A key future direction is the application of computational tools, such as physiologically based pharmacokinetic modeling and artificial-intelligence-based modeling, to streamline development and guide its clinical translation. Addressing these challenges through focused research and interdisciplinary collaboration will be essential to realizing the full therapeutic potential of melittin-based nanomedicines in oncology. Overall, this review synthesizes the findings from over 100 peer-reviewed studies published between 2008 and 2025, providing an up-to-date assessment of melittin-based nanomedicine strategies across diverse cancer types. Full article