Search Results (77)

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

Heat shock protein 70 (HSP70) represents a promising target for cancer therapy. Oncolytic vaccinia virus (oncoVV) mediates tumor regression through direct oncolysis and immune activation. However, the anti-tumor potential of HSP70-silenced oncoVV (oncoVV-shHSP70) remains unexplored. Here, we demonstrate that oncoVV-shHSP70 achieves superior tumor regression in ovarian cancer models (cell lines, immunodeficient mice and humanized mice) via dual mechanisms including enhancing apoptosis, autophagy flux, ROS generation, and immune reprogramming. Notably, we found that oncoVV-shHSP70 triggers an autophagy–ROS feedback loop that amplifies viral replication and pro-inflammatory cytokine expression. Crucially, in humanized mice, oncoVV-shHSP70 induced spatial redistribution of cytotoxic T cells, expanding tumor-infiltrating hCD8⁺hGZMB⁺ populations. These findings position oncoVV-shHSP70 as a promising viro-immunotherapy that co-opts HSP70 silencing to potentiate both direct oncolysis and anti-tumor immunity, providing a preclinical rationale for viro-immunotherapy in solid tumors. Full article

Background: Oncolytic virus (OV) therapy couples direct tumor lysis with systemic immune priming, yet clinical benefit remains heterogeneous and the predictive biomarker landscape is poorly defined. We undertook a systematic review and meta-analysis to quantify the efficacy and safety of OV therapy in solid tumors and to synthesize current evidence on response-modulating biomarkers. Methods: Following PRISMA 2020 guidelines, MEDLINE, Embase, Cochrane CENTRAL, ProQuest and Scopus were searched from inception to May 2025. Phase II–III randomized trials of genetically engineered or naturally occurring OV reporting objective response rate (ORR), progression-free survival (PFS), overall survival (OS) or biomarker data were eligible. Hazard ratios (HRs) or odds ratios (OR) were pooled with random-effects models; heterogeneity was assessed with I² statistics. Qualitative synthesis integrated genomic, immunologic and microbiome biomarkers. Results: Thirty-six trials encompassing around 4190 patients across different tumor types met inclusion criteria. Compared with standard therapy, OV-based regimens significantly improved ORR nearly three-fold (pooled OR = 2.77, 95% CI 1.85–4.16), prolonged PFS by 11% (HR = 0.89, 95% CI 0.80–0.99) and reduced mortality by 16% (OS HR = 0.84, 95% CI 0.72–0.97; I² = 59%). Benefits were most pronounced in melanoma (ORR 26–49%; OS HR 0.57–0.79) and in high-dose vaccinia virus for hepatocellular carcinoma (HR = 0.39). Grade ≥ 3 adverse events were not increased versus control (risk ratio 1.05, 95% CI 0.89–1.24); common toxicities were transient flu-like symptoms and injection-site reactions. Biomarker synthesis revealed that high tumor mutational burden, interferon-pathway loss-of-function mutations, baseline CD8⁺ T-cell infiltration, post-OV upregulation of IFN-γ/PD-L1, and favorable gut microbial signatures correlated with response, whereas intact antiviral signaling, immune-excluded microenvironments and myeloid dominance predicted resistance. Conclusions: OV therapy confers clinically meaningful improvements in tumor response, PFS and OS with a favorable safety profile. Integrating composite genomic–immune–microbiome biomarkers into trial design is critical to refine patient selection and realize precision viro-immunotherapy. Future research should prioritize biomarker-enriched, rational combination strategies to overcome resistance and extend benefit beyond melanoma. 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

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors, necessitating novel therapeutic approaches. Oncolytic treatments, particularly oncolytic viruses (OVs), have emerged as promising candidates by selectively infecting and lysing tumor cells while stimulating anti-tumor immunity. Various virus-based therapies are under investigation, including genetically engineered herpes simplex virus (HSV), adenovirus, poliovirus, reovirus, vaccinia virus, measles virus, and Newcastle disease virus, each exploiting unique tumor-selective mechanisms. While some, such as HSV-based therapies including G207 and Delytact^TM, have demonstrated clinical progress, significant challenges persist, including immune evasion, heterogeneity in patient response, and delivery barriers due to the blood–brain barrier. Moreover, combination strategies integrating OVs with immune checkpoint inhibitors, chemotherapy, and radiation are promising but require further clinical validation. Non-viral oncolytic approaches, such as tumor-targeting bacteria and synthetic peptides, remain underexplored. This review highlights current advancements while addressing critical gaps in the literature, including the need for optimized delivery methods, better biomarker-based patient stratification, and a deeper understanding of GBM’s immunosuppressive microenvironment. Future research should focus on enhancing OV specificity, engineering viruses to deliver therapeutic genes, and integrating OVs with precision medicine strategies. By identifying these gaps, this review provides a framework for advancing oncolytic therapies in GBM treatment. Full article

Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to metabolic plasticity and drug resistance. Oncolytic viruses (OVs), such as thymidine kinase-deleted vaccinia virus (oncoVV), selectively lyse tumors while stimulating antitumor immunity, however, their metabolic interplay with cancer cells is poorly understood. Here, we engineered an oncoVV-expressing Aphrocallistes vastus lectin (oncoVV-AVL) and uncovered its unique ability to exploit the ACSS2/TFEB axis, driving metabolic competition in HCC. In vitro, oncoVV-AVL triggered cell autophagy and lipid accumulation (3.4–5.7-fold upregulation of FASN and ACC1) while suppressing glucose uptake (41–63% higher extracellular glucose and 33–34% reduced lactate). Mechanistically, oncoVV-AVL upregulated acetyl-CoA synthetase 2 (ACSS2), promoting its nuclear translocation and interaction with transcription factor EB (TFEB) to concurrently activate lipogenesis and autophagic flux. The pharmacological inhibition of ACSS2 abolished these effects, confirming its central role. In vivo, oncoVV-AVL suppressed tumor growth while inducing lipid deposition (2-fold triglyceride increase), systemic hypoglycemia (42% glucose reduction), and autophagy activation (elevated LC3B-II/I ratios). This study establishes ACSS2 as a metabolic checkpoint in OV therapy, providing a rationale for combining oncolytic virotherapy with metabolic modulators in HCC. Full article

Oncolytic virotherapy is a rapidly evolving approach to cancer treatment. Our group previously designed VV-GMCSF-Lact, a recombinant oncolytic vaccinia virus targeting solid tumors including gliomas. In this study, we used single-cell RNA sequencing to compare transcriptional responses in human glioma cells, non-malignant brain cells, and immortalized glioblastoma U87 MG cells following infection with this oncolytic virus. We found that proneural glioblastoma cells and microglia-like cells from patient-derived glioma cultures were the most susceptible to VV-GMCSF-Lact. Increased expressions of histones, translational regulators, and ribosomal proteins positively correlated with viral load at the transcript level. Furthermore, higher viral loads were accompanied by a large-scale downregulation of genes involved in mitochondrial translation, metabolism, and oxidative phosphorylation. Levels of early vaccinia virus transcripts are also positively correlated with infection intensity, suggesting that the fate of cells is determined at the early stage of infection. Full article

Despite significant advances in cancer therapy, the prognosis for patients with advanced, disseminated disease remains poor. This underscores the urgent need for novel treatments that not only eliminate tumor cells effectively but also stimulate a strong, durable anti-cancer immune response. Among emerging strategies, oncolytic viruses have shown exceptional promise due to their selective cytotoxicity and their ability to activate T cell-mediated immune responses. In this review, we focus on the vaccinia virus (VACV), a member of the Poxviridae family, which has emerged as a leading candidate in modern oncolytic immunotherapy. We examine the virus’s properties that enable it to evade antiviral defenses and serve as a versatile, potent oncolytic agent. Furthermore, we explore its interactions with various components of the immune system and how these contribute to the induction of a robust T cell-driven response. Finally, we assess current efforts to harness VACV for the treatment of various cancer types and highlight future directions where its application is most likely to succeed. Overall, our goal is to present VACV as a powerful and broadly applicable platform with the potential to transform the landscape of oncology. Full article

Checkpoint inhibitor therapy revolutionized the treatment of patients with melanoma. However, in patients where melanoma exhibits resistance to checkpoint inhibitor therapy, the treatment options are limited. Oncolytic viruses are a unique form of immunotherapy that uses live viruses to infect and lyse tumor cells to release the elusive neoantigen picked up by the antigen-presenting cells, thus increasing the chances of an immune response against cancer. Coupled with checkpoint inhibitors, intratumoral injections of the oncolytic virus can help an enhanced immune response, especially in a tumor that displays resistance to checkpoint inhibitors. However, oncolytic viruses are not bereft of challenges and face several obstacles in the tumor microenvironment. From the historical use of wild viruses to the sophisticated use of genetically modified viruses in the current era, oncolytic virus therapy has evolved tremendously in the last two decades. Increasing the ability of the virus to select the malignant cells over the non-malignant ones, circumventing the antiviral immune response from the body, and enhancing the oncolytic properties of the viral platform by attaching various ligands are some of the several improvements made in the last three decades. In this manuscript, we trace the journey of the development of oncolytic virus therapy, especially in the context of melanoma. We review the clinical trials of talimogene laherparepvec in patients with melanoma. We also review the data available from the clinical trials of vusolimogene oderparepvec in patients with melanoma. Finally, we review the use of various oncolytic viruses and their challenges in clinical development. This manuscript aims to create a comprehensive literature review for clinicians to understand and implement oncolytic virus therapy in patients diagnosed with melanoma. Full article

This review provides an updated overview of oncolytic virotherapy as a promising therapeutic strategy for colorectal cancer (CRC), focusing on six key viral platforms: adenovirus, herpes simplex virus (HSV), reovirus, vesicular stomatitis virus (VSV), vaccinia virus (VV), and measles virus (MV). These viruses exhibit tumor-selective replication and exert their effects through mechanisms such as direct oncolysis, the delivery of immunostimulatory genes (e.g., IL-12, IL-15, GM-CSF), the activation of innate and adaptive immune responses, and the remodeling of the tumor microenvironment. Preclinical and early clinical studies suggest that oncolytic viruses can enhance the efficacy of existing treatments, particularly in immunologically “cold” tumors such as microsatellite stable CRC, when used in combination with chemotherapy or immune checkpoint inhibitors. Despite encouraging results, several challenges remain, including antiviral immune clearance, tumor heterogeneity, and limitations in systemic delivery. Current research focuses on improving viral engineering, enhancing tumor targeting, and designing combinatorial strategies to overcome resistance and maximize clinical benefits. Overall, oncolytic viruses represent a versatile and evolving therapeutic class with the potential to address unmet clinical needs in CRC. Full article

Background/Objectives: CAR T cell therapy, as a rapidly advancing immuno-oncology modality, has achieved significant success in the treatment of leukaemia and lymphoma. However, its application in solid tumours remains limited. The challenges include the heterogeneity of tumours, local immunosuppression, poor trafficking and infiltration, life-threatening toxicity and the lack of precise representative immunocompetent research models. Considering its typically dense and immunosuppressive tumour microenvironment (TME) and early metastasis, pancreatic ductal adenocarcinoma (PDAC) was employed as a model to address the challenges that hinder CAR T cell therapies against solid tumours and to expand immunotherapeutic options for advanced disease. Methods: A novel murine A20FMDV2 (A20) CAR T cell targeting integrin αvβ6 (mA20CART) was developed, demonstrating efficient and specific on-target cytotoxicity. The mA20CART cell as a monotherapy for orthotopic pancreatic cancer in an immunocompetent model demonstrated modest efficacy. Therefore, a novel triple therapy regimen, combining mA20CART cells with oncolytic vaccinia virus encoding IL-21 and a TGF-β-blocking antibody was evaluated in vivo. Results: The triple therapy improved overall survival, improved the safety profile of the CAR T cell therapy, attenuated metastasis and enhanced T cell infiltration. Notably, the potency of mA20CART was dependent on IL-2 supplementation. Conclusions: This study presents an αvβ6-targeting murine CAR T cell, offering a novel approach to developing CAR T cell technologies for solid tumours and a potential adjuvant therapy for pancreatic cancer. Full article

Objectives: Pancreatic cancer remains a therapeutic challenge due to its immunosuppressive microenvironment and treatment resistance. This study aimed to develop a novel recombinant oncolytic vaccinia virus (VVL-GL7) co-expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-7 (IL-7), designed to enhance anti-tumor immunity and synergize with immune checkpoint inhibitors. Methods: VVL-GL7 was constructed through CRISPR/Cas9-mediated knockout of TK and A49 genes, combined with the simultaneous insertion of dual cytokine-encoding cassettes. Anti-tumor efficacy was evaluated in vitro and in vivo using C57BL/6 mouse and Syrian hamster pancreatic cancer models. Comprehensive immune profiling evaluated CD8⁺ T-cell and macrophage infiltration dynamics while simultaneously assessing memory T-cell differentiation patterns using flow cytometry. Preclinical combination studies of VVL-GL7 and the PD-1 immune checkpoint inhibitor were systematically evaluated in a syngeneic pancreatic cancer model. Results: VVL-GL7 exhibited potent oncolytic activity, inducing significant tumor regression in both preclinical models. VVL-GL7 therapy significantly augmented CD8⁺ T-cell and macrophage infiltration within the tumor microenvironment, while concomitantly driving memory T-cell differentiation. The synergistic effects of VVL-GL7 and the PD-1 blockade further improved therapeutic outcomes, resulting in significantly higher tumor remission rates compared to monotherapy and achieving complete tumor regression in pancreatic cancer models. Conclusions: VVL-GL7 reprograms the immunosuppressive tumor microenvironment and synergizes with anti-PD-1 antibodies to overcome resistance in pancreatic cancer. Full article

The delivery of biomolecules to target cells has been a longstanding challenge in biotechnology. DNA viruses naturally evolved the ability to deliver genetic material to cells and modulate cellular processes. As such, they inherently possess requisite characteristics that have led to their extensive study, engineering, and development as biotechnological tools. Here, we overview the application of DNA viruses to biotechnology, with specific implications in basic research, health, biomanufacturing, and agriculture. For each application, we review how an increasing understanding of virology and technological methods to genetically manipulate DNA viruses has enabled advances in these fields. Additionally, we highlight the remaining challenges to unlocking the full biotechnological potential of DNA viral technologies. Finally, we discuss the importance of balancing continued technological progress with ethical and biosafety considerations. Full article

Ovarian cancer (OC) remains the most lethal gynecologic malignancy with limited effective treatment options. Oncolytic viruses (OVs) have emerged as a promising therapeutic approach for cancer treatment, capable of selectively infecting and lysing cancer cells while stimulating anti-tumor immune responses. Preclinical studies have demonstrated significant tumor regression and prolonged survival in OC models using various OVs, such as herpes simplex. Early-phase clinical trials have shown a favorable safety profile, though the impact on patient survival has been modest. Current research focuses on combining OVs with other treatments like immune checkpoint inhibitors to enhance their efficacy. We provide a comprehensive overview of the current understanding and future directions for utilizing OVs in the management of OC. Full article