Search Results (471)

Glioblastoma (GBM) is an aggressive and common form of central nervous system primary malignant tumor in adults. GBM accounts for about half of all gliomas. Despite maximal resection, radiotherapy, and temozolomide, median survival is still 12–15 months because of tumor heterogeneity, diffuse infiltration, and therapeutic resistance. Recurrence is nearly universal, underscoring the need for novel therapies. Oncolytic virotherapy demonstrates a promising strategy that combines direct tumor cell lysis with immune activation. Tumor-selective viruses replicate within malignant cells, induce cell death, and release tumor antigens, thereby reshaping the immunosuppressive microenvironment. Several viral backbones have advanced to clinical testing, including adenovirus (DNX-2401), herpes simplex virus (G47Δ, G207), poliovirus (PVS-RIPO), measles virus (MV-CEA), reovirus (pelareorep), vaccinia virus (Pexa-Vec), and vesicular stomatitis virus (VSV-GP). The approval of G47Δ in Japan for malignant glioma marks a milestone, with early trials demonstrating safety and signals of durable benefit, particularly in combination regimens. Current research emphasizes engineering viral genomes to enhance selectivity, immune stimulation, and resistance to clearance, while exploring synergistic combinations with radiotherapy, chemotherapy, immune checkpoint inhibitors, and tumor-treating fields. Advances in delivery, such as convection-enhanced infusion and blood–brain barrier modulation, are also under investigation. Despite obstacles, oncolytic virotherapy holds significant potential within multimodal GBM strategies. Full article

In the past decade, research on recombinant oncolytic viral agents in the treatment of solid tumors has evolved from the initial stage of simple genetic engineering to the current stage of multiple pipelines of parallel clinical application and combination therapy. Compared with T-VEC, the classical therapeutic agent that only expresses GM-CSF, which was approved in 2015, most new oncolytic virus designs include diverse gene constructs to reduce toxic effects, enhance multiple antitumor immunity, avoid immune clearance, or enhance tumor targeting. The single route of administration that activates the inflammatory tumor immune microenvironment by intratumoral injection is no longer sufficient to meet the treatment needs of refractory solid tumors. In this review, we illustrated the construction patterns of typical recombinant oncolytic viral agents and their latest clinical trial progress. Secondly, we summarized the underlying mechanisms of the combined application of antiviral and antitumor immunity in the field of solid tumor immunotherapy. Finally, we explored the feasibility of the intravenous application of oncolytic viruses and their future development directions. We believe that the diversified treatment design of oncolytic viruses will bring more surprises to the immunotherapy of refractory tumors. Full article

Oncolytic viruses represent an emerging class of therapeutic agents that have the potential to transform the care of patients with melanoma. In this narrative review, we describe the evolution of oncolytic virus approaches. We begin by describing early investigations using wild type viruses and then the development of sophisticated Herpes simplex virus 1 (HSV-1) variant constructs such as talimogene laherparepvec (T-VEC) and vusolimogene oderparepvec (Replimune-1, RP1), which incorporate deletions of viral genes and expression of human or synthetic transgenes to promote tumor selectivity, dendritic cell recruitment, antigen presentation, and stimulation of systemic anti-tumor immune responses. We review the status of clinical trials of oncolytic viruses in melanoma, highlight regulatory challenges, and describe important concepts and key remaining questions within the field. While T-VEC remains the only Food and Drug Administration (FDA)-approved oncolytic virus for melanoma treatment, ongoing research focusing on next-generation viral constructs and combination strategies aims to further improve clinical outcomes and expand the applicability of oncolytic virus therapy in melanoma. Full article

Cancer is a major challenge to global health, and its incidence rate and mortality are expected to continue to rise in the coming decades. Traditional treatment methods such as surgery, radiotherapy, and chemotherapy have limitations, which has prompted people to explore new treatment strategies. As a promising therapeutic approach, oncolytic viruses can selectively target and lyse tumor cells while avoiding damage to normal tissues. This article systematically reviews the mechanisms by which oncolytic viruses induce various forms of cell death, including apoptosis, autophagy, pyroptosis, necroptosis, and ferroptosis. We explored the direct killing effect of oncolytic viruses and their ability to activate local and systemic antitumor immunity, with a focus on the latest developments in the clinical application of oncolytic viruses, such as the development of novel recombinant viruses. In addition, we also analyzed strategies to enhance the efficacy of oncolytic viruses through gene modification, combination therapy, and targeted delivery systems. A deeper understanding of the multiple mechanisms of action of oncolytic viruses can help us develop more effective and personalized cancer treatment plans. Future research should focus on optimizing oncolytic viruses to overcome tumor drug resistance and improve patient prognosis, making them an important pillar of cancer treatment. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, marked by late diagnosis, limited responsiveness to conventional therapies, and an immunosuppressive tumor microenvironment. While immunotherapy has transformed treatment paradigms in several cancers, its efficacy in PDAC has been minimal. Oncolytic viruses and therapeutic cancer vaccines have emerged as promising immunotherapeutic strategies designed to stimulate robust, tumor-specific immune responses and reshape the immune landscape. However, despite encouraging preclinical data, clinical translation in PDAC has been largely disappointing. This review critically evaluates the design, delivery, and efficacy of oncolytic virotherapy and cancer vaccines in PDAC, examining barriers such as stromal desmoplasia, immune exclusion, and tumor heterogeneity. We also explore combination strategies integrating checkpoint inhibitors, chemotherapy, radiotherapy, and stromal modulation to overcome resistance. Ultimately, the viability of these approaches hinges on a clearer understanding of their mechanistic limitations and the refinement of delivery platforms. These factors will determine whether oncolytic viruses and cancer vaccines can be successfully repositioned within the therapeutic arsenal or warrant reevaluation in the evolving landscape of PDAC treatment. Full article

The overall survival rate of brain malignancies such as glioblastoma is currently a little under two years, at most, and treatment options for malignant brain tumors have demonstrated limited efficacy. The current standard of care to treat brain cancer includes surgical resection, radiation, and chemotherapy. Historically, an observed interaction between malignancies and concurrent viral infection has shown therapeutic potential that can perhaps be better leveraged in brain cancer with the technological advances that we have today. We aim to discuss a variety of viral vector designs to harness their oncolytic potential and explore how some of these ideas have performed in clinical trials. In our review, three major viral candidates that have gained traction in this field of research—Herpes simplex virus-1, adenovirus, and poliovirus—are highlighted. How the field has manipulated aspects of their virology and combined these viral platforms with other immune modulating strategies to treat both adult and pediatric tumors is also surveyed. Finally, the work exploring the possibility of other neurotropic viral candidates has been elaborated. More insight into the biological interactions between tumor, brain, and body is needed to address this particularly difficult clinical challenge. While there is still no clear, effective treatment for brain malignancies, the utilization of oncolytic viruses shows potential both as a treatment and as a tool to better understand the immune microenvironment of this pathology. Full article

Pediatric oral rhabdomyosarcoma (RMS) is a rare and aggressive cancer of the head and neck, characterized by a complex and mostly immunosuppressive tumor–immune microenvironment. Unlike adult cancers, pediatric RMS typically exhibits a “cold” immune profile, characterized by minimal T-cell infiltration, a low mutational burden, and resistance to immune checkpoint blockade. The tumor’s location in the oral cavity adds difficulty to treatment because of anatomical and functional limitations. Additionally, the presence of fusion oncogenes, such as PAX3:FOXO1, hampers immunogenicity and treatment response by disrupting antigen presentation and reducing immune cell infiltration. Advances in immuno-oncology have introduced new strategies, including immune checkpoint inhibitors, chimeric antigen receptor (CAR) therapies, cancer vaccines, and oncolytic viruses. However, these approaches face specific challenges in the pediatric population due to developmental immune factors. This narrative review highlights recent findings on the immunobiology of pediatric oral RMS, focusing on tumor–immune interactions and their impact on disease progression and treatment resistance. We reviewed the cellular components of the TIME, the mechanisms of immune evasion, and the expression of immune checkpoints, including PD-L1 and B7-H3. Emerging immunotherapies, including CAR-T, CAR-NK, and CAR-CIK cell therapies; checkpoint inhibitors; oncolytic viruses; and cancer vaccines, are discussed, with an emphasis on their current limitations and potential to transform the pediatric RMS immune landscape. Full article

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer (BC), comprising approximately 20% of newly diagnosed BC cases. The poor prognosis, high recurrence rates, and inefficacy of hormone-based therapies make TNBC one of the greatest challenges in contemporary oncology. The unique immunological features of TNBC, including relatively high tumor mutational burden, abundance of tumor-infiltrating lymphocytes, and elevated PD-L1 expression, offer a wide range of opportunities for immunotherapeutic approaches, of which the most progressive and promising are neoantigen-driven ones. This review examines the current landscape of neoantigen-based therapeutic approaches in TNBC treatment, spanning from discovery methodologies to clinical applications. We provide a critical analysis of the tumor microenvironment (TME) in TNBC, highlighting the balance between its immunoactivating (CD8+ T-cells, dendritic cells) and immunosuppressive (regulatory T-cells, M2 macrophages) components as the key determinant of therapeutic success, as well as reviewing the emerging approaches to TME reprogramming and recruiting in favor of better outcomes. We also present state-of the-art methods in neoantigen identification and prioritization, covering the landscape of technological platforms and prediction algorithms, addressing the existing accuracy limitations along with emerging computational solutions, and comprehensively discussing the TNBC neoantigen spectrum. Our analysis shows the strong domination of patient-specific (“private”) neoantigens over shared variants in the TNBC, with TP53 as the only gene with recurrent variants. Finally, we extensively cover neoantigen-recruiting therapeutic modalities including adoptive cell therapies, personalized vaccine platforms (peptide-based, mRNA/DNA vaccines, dendritic cell vaccines), and oncolytic viruses-based approaches. Our study of current clinical trials demonstrates the substantial gap between early proof-of-concept experiments and further applicability of neoantigen-driven therapies. The major challenges hampering the success of such methods include neoantigen prediction inaccuracy rates, high manufacturing costs, and time consumption. Promising ways to overcome these difficulties include the development of combinational strategies, TME modeling and modifying, and improvement of the therapy delivery properties, along with the optimization of production workflows and cost-effectiveness of vaccine development. Full article

The unique ability of oncolytic viruses (OVs) to replicate in and destroy malignant cells while leaving healthy cells intact and activating the host immune response makes them powerful targeted anti-cancer therapeutic agents. Vesicular stomatitis virus (VSV) only causes mild and asymptomatic infection, lacks pre-existing immunity, can be genetically engineered for enhanced efficiency and improved safety, and has a broad cell tropism. VSV can facilitate targeted delivery of immunostimulatory cytokines for an enhanced immune response against cancer cells, thus decreasing the possible toxicity frequently observed as a result of systemic delivery. In this study, the oncolytic potency of the two rVSV versions, rVSV-dM51-GFP, delivering green fluorescent protein (GFP), and rVSV-dM51-mIL12-mGMCSF, delivering mouse interleukin-12 (mIL-12) and granulocyte-macrophage colony-stimulating factor (mGMCSF), was compared on the four murine cancer cell lines of different origin and healthy mesenchymal stem cells (MSCs) at 24 h post-infection by flow cytometry. Lewis lung carcinoma (LL/2) cells were demonstrated to be more susceptible to the lytic effects of both rVSV versions compared to melanoma (B16-F10) cells. Detection of expression levels of antiviral and pro-apoptotic genes in response to the rVSV-dM51-GFP infection by quantitative PCR (qPCR) showed lower levels of IFIT, RIG-I, and N-cadherin and higher levels of IFNβ and p53 in LL/2 cells. Subsequently, C57BL/6 mice, infused subcutaneously with the LL/2 cells, were injected intratumorally with the rVSV-dM51-mIL12-mGMCSF 7 days later to assess the synergistic effect of rVSV and immunostimulatory factors. The in vivo study demonstrated that treatment with two rVSV-dM51-mIL12-mGMCSF doses 3 days apart resulted in a tumor growth inhibition index (TGII) of over 50%. Full article

Glioblastoma multiforme (GBM), the most aggressive primary brain tumor in adults, has a poor prognosis due to rapid recurrence and treatment resistance. This review examines the evolution of radiotherapy (RT) for GBM management, from whole-brain RT to modern techniques like intensity-modulated RT (IMRT) and volumetric modulated arc therapy (VMAT), guided by 2023 European Society for Radiotherapy and Oncology (ESTRO)-European Association of Neuro-Oncology (EANO) and 2025 American Society for Radiation Oncology (ASTRO) recommendations. The standard Stupp protocol (60 Gy/30 fractions with temozolomide [TMZ]) improves overall survival (OS) to 14.6 months, with greater benefits in O6-methylguanine-DNA methyltransferase (MGMT)-methylated tumors (21.7 months). Tumor Treating Fields (TTFields) extend median overall survival (mOS) to 31.6 months in MGMT-methylated patients and 20.9 months overall in supratentorial GBM (EF-14 trial). However, 80–90% of recurrences occur within 2 cm of the irradiated field due to tumor infiltration and radioresistance driven by epidermal growth factor receptor (EGFR) amplification, phosphatase and tensin homolog (PTEN) mutations, cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions, tumor hypoxia, and tumor stem cells. Pseudoprogression, distinguished using Response Assessment in Neuro-Oncology (RANO) criteria and positron emission tomography (PET), complicates response evaluation. Targeted therapies (e.g., bevacizumab; PARP inhibitors) and immunotherapies (e.g., pembrolizumab; oncolytic viruses), alongside advanced imaging (multiparametric magnetic resonance imaging [MRI], amino acid PET), support personalized RT. Ongoing trials evaluating reirradiation, hypofractionation, stereotactic radiosurgery, neoadjuvant therapies, proton therapy (PT), boron neutron capture therapy (BNCT), and AI-driven planning aim to enhance efficacy for GBM IDH-wildtype, but phase III trials are needed to improve survival and quality of life. Full article

Glioblastoma (GBM) is an aggressive brain tumor characterized by an immunosuppressive tumor microenvironment (TME), which contributes to treatment resistance and disease progression. Background: Tumor-associated macrophages (TAMs), comprising both resident microglia and bone marrow–derived macrophages, play a central role in supporting tumor growth, angiogenesis, and immune evasion. Most TAMs adopt an M2-like immunosuppressive phenotype, making them a promising target for immunomodulatory strategies in GBM. Method: According to PRISMA guidelines, we conducted a systematic literature review and recruited eligible studies focused on therapeutic approaches targeting TAMs in GBM, emphasizing mechanisms of action, efficacy, and challenges. Data extraction focused on therapeutic classes, outcomes, and TAM-related biomarkers. Results: We identified 30 studies meeting the inclusion criteria. These therapies are categorized into three main strategies: inhibition of TAM recruitment, enhancement of TAM-mediated phagocytosis, and reprogramming of TAMs. Combination strategies, including TAM-targeting with checkpoint inhibitors, nanoparticles, and oncolytic viruses, show synergistic effects in preclinical models. Conclusions: Targeting TAMs represents a multifaceted strategy for GBM treatment. Current evidence underscores the need for combination approaches integrating TAM modulation with existing standard-of-care therapies. Clinical translation remains limited due to challenges such as TAM heterogeneity, plasticity, immunosuppressive therapies, and restricted drug delivery across the blood–brain barrier. Future directions should highlight personalized treatments based on detailed TME profiling. Combining TAM-targeted therapies with agents modulating metabolic or immune pathways, and leveraging advanced delivery systems and spatial transcriptomics may improve efficacy. Full article

Objectives: Despite advancements in molecular-targeted therapies and immune checkpoint inhibitors, the survival rate of patients with advanced lung cancer remains unsatisfactory. Therefore, new and effective treatment strategies are urgently needed. Both mesenchymal-epithelial transition (MET) inhibitors and oncolytic viruses exhibit immunomodulatory properties along with direct antitumor effects. Materials and Methods: The antitumor effects of a combination therapy using MDRVV, a modified vaccinia virus for oncolytic virus therapy, and tepotinib, a MET inhibitor, were evaluated in vitro and in vivo using lung cancer models. Results: The combination therapy demonstrated additive cytotoxic effects on various lung cancer cell lines in vitro and significantly suppressed tumor growth in an immunocompetent mouse model. MDRVV triggered immunogenic cell death, evidenced by the release of adenosine triphosphate (ATP) and high-mobility group box-1 (HMGB-1). Additionally, the combination therapy enhanced CD4+ and CD+ T-cell infiltration more effectively than either agent alone. MDRVV exhibited antitumor effects not only in the inoculated tumors but also in distant tumors, with the most pronounced effect observed when combined with tepotinib. Conclusions: These findings suggest that combining a MET inhibitor with oncolytic vaccinia virus represents a promising and effective strategy for improving lung cancer treatment by targeting both tumor cells and the tumor microenvironment. Full article

Despite advances in immunotherapy with checkpoint inhibitors, a significant proportion of patients with head and neck squamous cell carcinoma (HNSCC) do not respond to treatment or eventually develop resistance. This review focuses on novel therapeutic strategies currently under investigation for HNSCC, moving beyond the established paradigms of EGFR inhibition and PD-1/PD-L1 blockade. We explore emerging targets and drug classes, including next-generation immunotherapies, targeted therapies directed at specific molecular alterations, epigenetic modifiers, agents targeting the tumor microenvironment, and innovative approaches like cell-based therapies and oncolytic viruses. We discuss the preclinical rationale and clinical data (where available) for these novel approaches, highlighting the challenges and opportunities in translating these discoveries into improved outcomes for patients with HNSCC. 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

Conventional immunotherapy, including immune checkpoint blockade and chimeric antigen receptor (CAR)-T cells, has revolutionized cancer therapy over the past decade. Yet, the efficacy of these therapies is limited by tumor resistance, antigen escape mechanisms, poor persistence, and T-cell exhaustion, particularly in the treatment of solid tumors. The emergence of unconventional immunotherapies offers novel opportunities by leveraging diverse immune cell subsets and synthetic biologics. This review explores various immunotherapy platforms, including gamma delta T cells, invariant natural killer T cells, mucosal-associated invariant T cells, engineered regulatory T cells, and universal CAR platforms. Additionally, it expands on biologics, including bispecific and multispecific antibodies, cytokine fusions, agonists, and oncolytic viruses, showcasing their potential for modular engineering and off-the-shelf applicability. Distinct features of unconventional platforms include independence from the major histocompatibility complex (MHC), tissue-homing capabilities, stress ligand sensing, and the ability to bridge adaptive and innate immunity. Their compatibility with engineering approaches highlights their potential as scalable, efficient, and cost-effective therapies. To overcome translational challenges such as functional heterogeneity, immune exhaustion, tumor microenvironment-mediated suppression, and limited persistence, novel strategies will be discussed, including metabolic and epigenetic reprogramming, immune cloaking, gene editing, and the utilization of artificial intelligence for patient stratification. Ultimately, unconventional immunotherapies extend the therapeutic horizon of cancer immunotherapy by breaking barriers in solid tumor treatment and increasing accessibility. Continued investments in research for mechanistic insights and scalable manufacturing are key to unlocking their full clinical potential. Full article