Colorectal cancer (CRC) is a leading health issue and treatments to eradicate it, such as conventional chemotherapy, are non‑selective and come with a number of complications. The present review focuses on the relatively new area of precision oncolytic viral therapy (OVT), with genetic targeting and immune modifications that offer a new future for CRC treatment. In the present review, an overview of the selection factors that are considered optimal for an oncolytic virus, mechanisms of oncolysis and immunomodulation applied to the OVT, as well as new strategies to improve the efficacy of this method are described. Additionally, cause‑and‑effect relationships are examined for OVT efficacy, mediated by the tumor microenvironment, and directions for genetic manipulation of viral specificity are explored. The possibility of synergy between OVT and immune checkpoint inhibitors and other treatment approaches are demonstrated. Incorporating the details of the present review, biomarker‑guided combination therapies in precision OVT for individualized CRC care, significant issues and future trends in this required area of medicine are highlighted. Increasingly, OVT is leaving the experimental stage and may become routine practice; it provides a new perspective on overcoming CRC and highlights the importance of further research and clinical work.

Cancer immunotherapy, encompassing both experimental and standard-of-care therapies, has emerged as a promising approach to harnessing the immune system for tumor suppression. Experimental strategies, including novel immunotherapies and preclinical models, are actively being explored, while established treatments, such as immune checkpoint inhibitors (ICIs), are widely implemented in clinical settings. This comprehensive review examines the historical evolution, underlying mechanisms, and diverse strategies of cancer immunotherapy, highlighting both its clinical applications and ongoing preclinical advancements. The review delves into the essential components of anticancer immunity, including dendritic cell activation, T cell priming, and immune surveillance, while addressing the challenges posed by immune evasion mechanisms. Key immunotherapeutic strategies, such as cancer vaccines, oncolytic viruses, adoptive cell transfer, and ICIs, are discussed in detail. Additionally, the role of nanotechnology, cytokines, chemokines, and adjuvants in enhancing the precision and efficacy of immunotherapies were explored. Combination therapies, particularly those integrating immunotherapy with radiotherapy or chemotherapy, exhibit synergistic potential but necessitate careful management to reduce side effects. Emerging factors influencing immunotherapy outcomes, including tumor heterogeneity, gut microbiota composition, and genomic and epigenetic modifications, are also examined. Furthermore, the molecular mechanisms underlying immune evasion and therapeutic resistance are analyzed, with a focus on the contributions of noncoding RNAs and epigenetic alterations, along with innovative intervention strategies. This review emphasizes recent preclinical and clinical advancements, with particular attention to biomarker-driven approaches aimed at optimizing patient prognosis. Challenges such as immunotherapy-related toxicity, limited efficacy in solid tumors, and production constraints are highlighted as critical areas for future research. Advancements in personalized therapies and novel delivery systems are proposed as avenues to enhance treatment effectiveness and accessibility. By incorporating insights from multiple disciplines, this review aims to deepen the understanding and application of cancer immunotherapy, ultimately fostering more effective and widely accessible therapeutic solutions.

Breast cancer is the most prevalent malignant tumor among women, with triple-negative breast cancer (TNBC) being one of the most aggressive forms due to its high invasiveness and metastatic potential. Traditional treatments such as endocrine therapy and anti-HER2-targeted therapy are largely ineffective for TNBC, and while chemotherapy shows some promise, resistance remains a significant hurdle. Recently, there has been increasing interest in biological therapies, especially oncolytic viruses (OVs). OVs promote anti-tumor effects by selectively killing tumor cells and stimulating immune responses, and have achieved notable breakthroughs in breast cancer treatment. OVs have demonstrated effectiveness comparable to surgery, radiotherapy, or chemotherapy in selected cancers, but data are sparse in the context of TNBC. This review provides an overview of recent progress in the application of OVs as a tool for precision TNBC treatment.

KD01, a third-generation conditionally replicating adenovirus serotype 5 developed by our team, has approved by the China Center for Drug Evaluation (CDE) for Phase I clinical trials (NCT06552598). However, 60% seroprevalence of anti-Ad5 neutralizing antibodies is a major hurdle for Ad5-based oncolytic viruses. To address this issue, we developed oAd5/35-HF, a fourth-generation oncolytic adenovirus vector designed to enhance infection efficiency and evade pre-existing neutralizing antibodies (NABs). To achieve this, we introduced targeted capsid modifications, replacing hexon hypervariable regions (HVRs) 1 and 5 with those from adenovirus serotype 35 (Ad35), along with alterations to the fiber region. These combined modifications significantly improved infection efficiency, maintained high viral titers, and enabled the virus to resist NABs. This is the first report of replacing both the Ad5 hexon HVRs and fiber regions with those from Ad35 in an oncolytic adenovirus, resulting in potent antitumor activity across multiple cancer types, even in the presence of high NAB levels. The oAd5/35-HF backbone provides a versatile platform for developing new chimera oncolytic adenovirus and adenovirus vector-based vaccine.

Among various therapeutic agents, Oncolytic Viruses (OVs) are the most promising anticancer therapeutics because of their tumor-specific targeting and capability to mediate an antitumor immune response. In this review, we will discuss how epigenetic reprogramming of both the host and tumor can facilitate increased sensitivity of tumors to OV therapy. OVs infect tumor cells and modulate epigenetic landscapes, including DNA methylation, histone modifications, and chromatin remodeling, as well as non-coding RNA expression that consequently induces immune responses. These epigenetic changes, including hypermethylation of tumor-associated antigen genes and chromatin accessibility alterations, enhance the immunogenicity of tumors to facilitate recognition by the immune system. Here, we provide a general review addressing this question by discussing the potential benefits of combining OVs with epigenetic drugs to combat resistance and promote treatment efficacy. This information illustrates the importance of personalized OV therapy regarding epigenome in individual profiles and transitions. Still, it extends difficulty in inducing with acquisitions of viral-induced changes globally and making translatable steps by creating cancer-specific predictive treatment models.

Understanding the modulation of specific immune cells within the tumor microenvironment (TME) offers new hope in cancer treatments, especially in cancer immunotherapies. In recent years, immune modulation and resistance to immunotherapy have become critical challenges in cancer treatments. However, novel strategies for immune modulation have emerged as promising approaches for oncology due to the vital roles of the immunomodulators in regulating tumor progression and metastasis and modulating immunological responses to standard of care in cancer treatments. With the progress in immuno-oncology, a growing number of novel immunomodulators and mechanisms are being uncovered, offering the potential for enhanced clinical immunotherapy in the near future. Thus, gaining a comprehensive understanding of the broader context is essential. Herein, we particularly summarize the paradoxical role of tumor-related immune cells, focusing on how targeted immune cells and their actions are modulated by immunotherapies to overcome immunotherapeutic resistance in tumor cells. We also highlight the molecular mechanisms employed by tumors to evade the long-term effects of immunotherapeutic agents, rendering them ineffective.

Cancer, characterized by the uncontrolled proliferation of cells, is one of the leading causes of death globally, with approximately one in five people developing the disease in their lifetime. While many driver genes were identified decades ago, and most cancers can be classified based on morphology and progression, there is still a significant gap in knowledge about genetic aberrations and nuclear DNA damage. The study of two critical groups of genes-tumor suppressors, which inhibit proliferation and promote apoptosis, and oncogenes, which regulate proliferation and survival-can help to understand the genomic causes behind tumorigenesis, leading to more personalized approaches to diagnosis and treatment. Aberration of tumor suppressors, which undergo two-hit and loss-of-function mutations, and oncogenes, activated forms of proto-oncogenes that experience one-hit and gain-of-function mutations, are responsible for the dysregulation of key signaling pathways that regulate cell division, such as p53, Rb, Ras/Raf/ERK/MAPK, PI3K/AKT, and Wnt/β-catenin. Modern breakthroughs in genomics research, like next-generation sequencing, have provided efficient strategies for mapping unique genomic changes that contribute to tumor heterogeneity. Novel therapeutic approaches have enabled personalized medicine, helping address genetic variability in tumor suppressors and oncogenes. This comprehensive review examines the molecular mechanisms behind tumor-suppressor genes and oncogenes, the key signaling pathways they regulate, epigenetic modifications, tumor heterogeneity, and the drug resistance mechanisms that drive carcinogenesis. Moreover, the review explores the clinical application of sequencing techniques, multiomics, diagnostic procedures, pharmacogenomics, and personalized treatment and prevention options, discussing future directions for emerging technologies.

Malignant ascites (MA) develops when malignant disease of the peritoneum causes excess fluid to accumulate in the abdominal cavity. It portends a poor prognosis and is associated with debilitating symptoms. While several palliative therapies exist, none have proven curative or free from side effects and complications. This review article describes experimental therapies on the horizon and the contemporary management of MA.

A literature review was performed using MEDLINE/PubMed, in which studies of emerging or experimental therapies under investigation for the management of MA were reviewed. Current therapies were also reviewed to provide important context. Data, including study design, sample size, primary and secondary outcomes, and side effects were recorded and described. Studies were then categorized into distinct sections and subsections, with tables corresponding to each section.

Five current therapies, including paracentesis, diuretics, peritoneovenous shunting, permanent catheters, and intraperitoneal chemotherapy, are described. Their limitations in effectively managing MA are highlighted. The "Experimental therapies" section is subsectioned into several categories, with the major studies corresponding to each section thoroughly described regarding methods, results, and validity. A final section describes treatments for mucinous ascites, which has distinct characteristics.

While each of the experimental therapies described offers unique benefits and has demonstrated some promise in managing MA, they all have limitations that have thus far prevented any one of them from being routinely used in practice. MA remains a challenging condition to treat, warranting further research into novel therapies.

Oncolytic viruses represent a distinct class of viruses that selectively infect and destroy tumor cells while sparing normal cells. Despite their potential, oncolytic viruses encounter several challenges as standalone therapies. Consequently, the combination of oncolytic viruses with other therapeutic modalities has emerged as a prominent research focus. This paper summarizes the tumor-killing mechanisms of oncolytic viruses, explores their integration with radiotherapy, chemotherapy, immune checkpoint inhibitors, CAR-T, and CAR-NK therapies, and provides an overview of related clinical trials. By synthesizing these advancements, this study seeks to offer valuable insights for the clinical translation of oncolytic virus combination therapies.

Oncolytic virotherapy has emerged as a promising immunotherapy strategy against cancer. As the first picornavirus tested in humans for its oncolytic potential, Senecavirus A (SVA) possesses several advantageous features, including its small size, rapid replication, and ability to penetrate the vascular system of solid tumors, allowing for the specific targeting and lysis of tumor cells. Additionally, SVA does not integrate into the host genome, thus avoiding potential genomic damage, and it lacks oncogenes or other virulence genes. Importantly, no significant pathogenic effects have been observed in humans or companion animals. Due to its simple genetic structure, SVA is amenable to various genetic modifications, allowing it to carry exogenous genes to further enhance tumor therapy. This review summarizes current knowledge of SVA's mechanisms of action and its progress in oncolytic therapy research, while also addressing the challenges and future directions.

Oncolytic virus (OV) mediated immunotherapy is one of the recent techniques used to treat higher grade cancers where conventional therapies like chemotherapy, radiation fail. OVs as a therapeutic tool show high efficacy and fewer side effects than conventional methods as supported by multiple preclinical and clinical studies since they are engineered to target tumours. In this chapter, we discuss the modifications in viruses to make them oncolytic, types of strains commonly administered, mechanisms employed by viruses to specifically target and eradicate malignancy and progress achieved as reported in case studies (preclinical and clinical trials). OVs also face some unique challenges with respect to the malignancy being treated and the varied pathogen exposure of the patients, which is also highlighted here. Since pathogen exposure varies according to population dynamics worldwide, chances of generating a non-specific recall response to an OV cannot be negated. Lastly, the future perspectives and ongoing practises of combination therapies are discussed as they provide a leading edge over monotherapies in terms of tumour clearance, blocking metastasis and enhancing patient survival. Efforts undertaken to overcome current challenges are also highlighted.

Although cancer therapy has significantly advanced in recent decades, patients and healthcare professionals are still quite concerned about adverse effects due to the non-targeted nature of currently used chemotherapeutics. Results obtained in a large number of recently published experimental studies indicated that mesenchymal stem-cell-derived exosomes (MSC-Exos), due to their biocompatibility, ability to cross biological barriers, and inherent targeting capabilities, could be used as a promising drug-delivery system for anti-cancer therapies. Their lipid bilayer protects cargo of anti-cancer drugs, making them excellent candidates for the delivery of therapeutic agents. MSC-Exos could be engineered to express ligands specific for tumor cells and, therefore, could selectively deliver anti-cancer agents directly in malignant cells, minimizing side effects associated with chemotherapeutic-dependent injury of healthy cells. MSC-Exos can carry multiple therapeutic agents, including anti-cancer drugs, micro RNAs, and small bioactive molecules, which can concurrently target multiple signaling pathways, preventing tumor growth and progression and overcoming resistance of tumor cells to many standard chemotherapeutics. Accordingly, in this review article, we summarized current knowledge and future perspectives about the therapeutic potential of MSCs-Exos in anti-cancer treatment, opening new avenues for the targeted therapy of malignant diseases.

Immunotherapy has become a crucial strategy in cancer treatment, but its effectiveness is often constrained. Most cancer immunotherapies focus on stimulating T-cell-mediated immunity by driving the cancer-immunity cycle, which includes tumor antigen release, antigen presentation, T cell activation, infiltration, and tumor cell killing. However, metabolism reprogramming in the tumor microenvironment (TME) supports the viability of cancer cells and inhibits the function of immune cells within this cycle, presenting clinical challenges. The distinct metabolic needs of tumor cells and immune cells require precise and selective metabolic interventions to maximize therapeutic outcomes while minimizing adverse effects. Recent advances in nanotherapeutics offer a promising approach to target tumor metabolism reprogramming and enhance the cancer-immunity cycle through tailored metabolic modulation. In this review, we explore cutting-edge nanomaterial strategies for modulating tumor metabolism to improve therapeutic outcomes. We review the design principles of nanoplatforms for immunometabolic modulation, key metabolic pathways and their regulation, recent advances in targeting these pathways for the cancer-immunity cycle enhancement, and future prospects for next-generation metabolic nanomodulators in cancer immunotherapy. We expect that emerging immunometabolic modulatory nanotechnology will establish a new frontier in cancer immunotherapy in the near future.

Oncolytic virotherapy (OVT) is a promising option for cancer treatment. OVT involves selective oncolytic virus (OV) replication within cancer cells, which triggers anti-tumor responses and immunostimulation. Despite promising potential, OVT faces critical challenges, including insufficient tumor-specific targeting, which results in limited tumor penetration and variability in therapeutic efficacy. These challenges are particularly pronounced in solid tumors with complex microenvironments and heterogeneous vascularization. A comprehensive research program is currently underway to develop and refine innovative delivery methods to address these issues to enhance OVT precision and efficacy. A principal area of investigation is the utilization of cellular carriers to enhance the delivery and distribution of OVs within tumor microenvironments, thereby optimizing immune system activation and maximizing anti-tumor effects. This review offers a comprehensive overview of the current strategies that are being used to enhance the delivery of OVs via cellular carriers with the goal of improving the clinical impact of OVT in cancer therapy.

Despite enormous progress, advanced cancers are still one of the most serious medical problems in current society. Although various agents and therapeutic strategies with anticancer activity are known and used, they often fail to achieve satisfactory long-term patient outcomes and survival. Recently, immunotherapy has shown success in patients by harnessing important interactions between the immune system and cancer. However, many of these therapies lead to frequent side effects when administered systemically, prompting treatment modifications or discontinuation or, in severe cases, fatalities. New therapeutic approaches like intratumoral immunotherapy, characterized by reduced side effects, cost, and systemic toxicity, offer promising prospects for future applications in clinical oncology. In the context of locally advanced or metastatic cancer, combining diverse immunotherapeutic and other treatment strategies targeting multiple cancer hallmarks appears crucial. Such combination therapies hold promise for improving patient outcomes and survival and for promoting a sustained systemic response. This review aims to provide a current overview of immunotherapeutic approaches, specifically focusing on the intratumoral administration of drugs in patients with locally advanced and metastatic cancers. It also explores the integration of intratumoral administration with other modalities to maximize therapeutic response. Additionally, the review summarizes recent advances in intratumoral immunotherapy and discusses novel therapeutic approaches, outlining future directions in the field.

Immunotherapy is emerging as a novel and reliable therapeutic technique for treating diseases such as autoimmunity, HIV/AIDS, allergy and cancers. This approach works by modulating the patient's immune system, activating both the innate and humoral branches to combat life-threatening diseases. The foundation of immunotherapy began with the discovery and development of "serum therapy" by German physiologist Emil Von Behring who received the Nobel Prize in 1901 for his contributions to the treatment of diphtheria. Around the same time, Dr. William Coley expanded the field for cancer treatment by developing the first immune based cure for sarcomas using attenuated strains of bacteria injected directly into patient's tumours. As medical science advanced, a broader understanding of the immune system and its components led to the emergence of different immunotherapeutic techniques. These include adoptive cell transfer therapy, cytokine therapy, cancer vaccines, and antibody-drug conjugates. The chapter provides a comprehensive understanding of the history and the current techniques used in immunotherapy, detailing the principles behind their mechanisms and the types of diseases tackled by each immunotherapeutic technique. By examining the journey from early discoveries to modern advancements, the chapter highlights the transformative impact of immunotherapy on medical science and patient care.

Oncolytic viruses (OVs) are a promising therapeutic approach for cancer, although their systemic administration faces significant challenges. Mesenchymal stem cells have emerged as potential carriers to overcome these obstacles due to their tumor-tropic properties. This study investigates the use of menstrual blood-derived mesenchymal stem cells (MenSCs) as carriers for OVs in cancer therapy, focusing on enhancing their efficacy through different culture conditions. MenSCs were isolated from donors of different ages and cultured under normoxic and hypoxic conditions, with varying adherence capacities. Hypoxic conditions significantly improved MenSCs proliferation and tumor migration capabilities, as demonstrated by proliferation assays and RNA-sequencing analysis, which revealed upregulation of genes related to cell division and tumor tropism. In vivo studies using a lung adenocarcinoma mouse model confirmed that hypoxia-conditioned MenSCs had superior tumor-homing abilities. The study also demonstrated the feasibility of establishing a master and working cell bank from a single menstrual blood donation. These findings suggest that hypoxia-conditioned MenSCs could be highly effective as OV carriers, potentially leading to better clinical outcomes in cancer treatment by enhancing tumor targeting and therapeutic efficacy.

Head and neck cancer (HNC) represents a challenging oncological entity with significant morbidity and mortality rates. Despite advances in conventional therapies, including surgery, chemotherapy, and radiation therapy, the overall survival rates for advanced HNC remain suboptimal. In recent years, the emerging field of oncolytic virotherapy has gained attention as a promising therapeutic approach for various malignancies, including HNC. This review provides a comprehensive overview of the current understanding of oncolytic viruses (Ovs) in the context of HNC treatment, including their mechanisms of action, preclinical and clinical studies, challenges, and future directions. Future oncolytic virotherapy focuses on improving delivery and specificity through nanoparticle carriers and genetic modifications to enhance tumor targeting and immune response. Combining different OVs and integrating them with immunotherapies, such as checkpoint inhibitors, could overcome tumor resistance and improve outcomes. Personalized approaches and rigorous clinical trials are key to ensuring the safety and effectiveness of virotherapy in treating HNC.

Immuno-oncology (IO) is a growing strategy in cancer treatment. Oncolytic viruses (OVs) can selectively infect cancer cells and lead to direct and/or immune-dependent tumor lysis. This approach represents an opportunity to potentiate the efficacy of immune checkpoint inhibitors (ICI), such as pembrolizumab. Currently, there is a lack of comprehensive quantitative models for the aforementioned scenarios. In this work, we developed a mechanistic framework describing viral kinetics, viral dynamics, and tumor response after intratumoral (i.t.) or intravenous (i.v.) administration of V937 alone or in combination with pembrolizumab. The model accounts for tumor shrinkage, in both injected and non-injected lesions, induced by: viral-infected tumor cell death and activated CD8 cells. OV-infected tumor cells enhanced the expansion of CD8 cells, whereas pembrolizumab inhibits their exhaustion by competing with PD-L1 in their binding to PD-1. Circulating viral levels and treatment effects on tumor volume were adequately characterized in all the different scenarios. This mechanistic-based model has been developed by combining top-down and bottom-up approaches and provides individual estimates of viral and ICI responses. The robustness of the model is reflected by the description of the tumor size time profiles in a variety of clinical scenarios. Additionally, this platform allows us to investigate not only the contribution of processes related to the viral kinetics and dynamics on tumor response, but also the influence of its interaction with an ICI. Additionally, the model can be used to explore different scenarios aiming to optimize treatment combinations and support clinical development.

Oncolytic viruses (OVs) represent a targeted anti-cancer therapy approach due to their ability not only to selectively infect and destroy malignant cells but also to induce an immune response. Vesicular stomatitis virus (VSV) offers a promising platform due to its low prevalence and pathogenicity in humans, lack of pre-existing immunity, easily manipulated genome, rapid growth to high titers in a broad range of cell lines, and inability to integrate into the host genome. However, despite its many advantages, many unresolved problems remain: problematic production based on the reverse genetics system, oncological selectivity, and the overall effectiveness of VSV monotherapy. This review will discuss various attempts at viral genome modifications aimed at improving the oncolytic properties of VSV. These strategies include inhibition of viral genes, modification of genes responsible for targeting cancer cells over healthy ones, insertion of foreign genes for boosting immune response, and changing the order of viral and inserted foreign genes. In addition, possible ways to improve VSV-based anti-tumor therapy and achieve higher efficiency will be considered by evaluating the effectiveness of various delivery methods as well as discussing treatment options by combining VSV with other groups of anticancer drugs.

Oncolytic viruses (OVs) are an emerging immunotherapy platform that selectively target tumour cells, inducing immunogenic cell death. This reverses the 'immune-desert' phenotype of tumours, enhancing antitumour immunity. However, oncolytic virotherapy has shown limited efficacy in solid tumours due to the presence of protumoural, immunosuppressive cancer-associated fibroblasts (CAFs). Recent studies have explored OVs that specifically target CAFs to enhance antitumoural immune responses, with promising results. Nevertheless, detailed interrogation of the experimental design of these studies casts doubt on their potential for successful clinical translation. Most studies targeted CAFs non-specifically, failing to acknowledge CAF heterogeneity, with antitumoural CAFs also present. Thus, use of transcriptomics is advisable to provide more focused targeting, limiting potential off-target toxicity. Furthermore, experiments to date have largely been conducted in murine models that do not faithfully recapitulate tumour microenvironments, potentially biasing the efficacy observed. Future work should make use of humanised patient-derived xenograft murine models for animal studies, after which primary human tumour biopsies should be utilised to more closely represent the patient population for maximal translation relevance. Additionally, approaches to enhance the antitumoural immune responses of this therapy should be prioritised, with the ultimate aim of achieving complete remission, which has not yet been observed pre-clinically.

Systemic delivery of oncolytic adenovirus (oAd) for cancer gene therapy must overcome several limitations such as rapid clearance from the blood, nonspecific accumulation in the liver, and insufficient delivery to the tumor tissues. In the present report, a tumor microenvironment-triggered artificial lipid envelope composed of a pH-responsive sulfamethazine-based polymer (PUSSM)-conjugated phospholipid (DOPE-HZ-PUSSM) and another lipid decorated with epidermal growth factor receptor (EGFR) targeting peptide (GE11) (GE11-DOPE) was utilized to encapsulate replication-incompetent Ad (dAd) or oAd coexpressing short-hairpin RNA (shRNA) against Wnt5 (shWnt5) and decorin (dAd/LP-GE-PS or oAd/LP-GE-PS, respectively). In vitro studies demonstrated that dAd/LP-GE-PS transduced breast cancer cells in a pH-responsive and EGFR-specific manner, showing a higher level of transduction than naked Ad under a mildly acidic pH of 6.0 in EGFR-positive cell lines. In vivo biodistribution analyses revealed that systemic administration of oAd/LP-GE-PS leads to a significantly higher level of intratumoral virion accumulation compared to naked oAd, oAd encapsulated in a liposome without PUSSM or EGFR targeting peptide moiety (oAd/LP), or oAd encapsulated in a liposome with EGFR targeting peptide alone (oAd/LP-GE) in an EGFR overexpressing MDA-MB-468 breast tumor xenograft model, showing that both pH sensitivity and EGFR targeting ability were integral to effective systemic delivery of oAd. Further, systemic administration of all liposomal oAd formulations (oAd/LP, oAd/LP-GE, and oAd/LP-GE-PS) showed significantly attenuated hepatic accumulation of the virus compared to naked oAd. Collectively, our findings demonstrated that pH-sensitive and EGFR-targeted liposomal systemic delivery of oAd can be a promising strategy to address the conventional limitations of oAd to effectively treat EGFR-positive cancer in a safe manner.

Cancer is one of the leading causes of death worldwide. Traditional cancer treatments include surgery, radiotherapy, and chemotherapy, as well as combinations of these treatments. Despite significant advances in these fields, the search for innovative ways to treat malignant tumors, including the application of oncolytic viruses, remains relevant. One such virus is the vesicular stomatitis virus (VSV), which possess a number of useful oncolytic properties. However, VSV-based drugs are still in their infancy and are yet to be approved for clinical use. This review discusses the mechanisms of oncogenesis, the antiviral response of tumor and normal cells, and markers of tumor cell resistance to VSV virotherapy. In addition, it examines methods for producing and arming recombinant VSV and provides examples of clinical trials. The data presented will allow better assessment of the prospects of using VSV as an oncolytic.

We model interactions between cancer cells and viruses during oncolytic viral therapy. One of our primary goals is to identify parameter regions that yield treatment failure or success. We show that the tumor size under therapy at a particular time is less than the size without therapy. Our analysis demonstrates two thresholds for the horizontal transmission rate: a "failure threshold" below which treatment fails, and a "success threshold" above which infection prevalence reaches 100% and the tumor shrinks to its smallest size. Moreover, we explain how changes in the virulence of the virus alter the success threshold and the minimum tumor size. Our study suggests that the optimal virulence of an oncolytic virus depends on the timescale of virus dynamics. We identify a threshold for the virulence of the virus and show how this threshold depends on the timescale of virus dynamics. Our results suggest that when the timescale of virus dynamics is fast, administering a more virulent virus leads to a greater reduction in the tumor size. Conversely, when the viral timescale is slow, higher virulence can induce oscillations with high amplitude in the tumor size. Furthermore, we introduce the concept of a "Hopf bifurcation Island" in the parameter space, an idea that has applications far beyond the results of this paper and is applicable to many mathematical models. We elucidate what a Hopf bifurcation Island is, and we prove that small Islands can imply very slowly growing oscillatory solutions.

Oncolytic viruses (OVs) have emerged as a powerful tool in cancer therapy. Characterized with the unique abilities to selectively target and lyse tumor cells, OVs can expedite the induction of cell death, thereby facilitating effective tumor eradication. Nanoengineering-derived OVs overcome traditional OV therapy limitations by enhancing the stability of viral circulation, and tumor targeting, promising improved clinical safety and efficacy and so on. This review provides a comprehensive analysis of the multifaceted mechanisms through which engineered OVs can suppress tumor progression. It initiates with a concise delineation on the fundamental attributes of existing OVs, followed by the exploration of their mechanisms of the antitumor response. Amid rapid advancements in nanomedicine, this review presents an extensive overview of the latest developments in the synergy between nanomaterials, nanotechnologies, and OVs, highlighting the unique characteristics and properties of the nanomaterials employed and their potential to spur innovation in novel virus design. Additionally, it delves into the current challenges in this emerging field and proposes strategies to overcome these obstacles, aiming to spur innovation in the design and application of next-generation OVs.

Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptors (ERs), human epidermal growth factor receptor 2 (HER2), and progesterone receptors (PRs). TNBC has the poorest prognosis among breast cancer subtypes and is more likely to respond to immunotherapy due to its higher expression of PD-L1 and a greater percentage of tumor-infiltrating lymphocytes. Immunotherapy has revolutionized TNBC treatment, especially with the FDA's approval of pembrolizumab (Keytruda) combined with chemotherapy for advanced cases, opening new avenues for treating this deadly disease. Although immunotherapy can significantly improve patient outcomes in a subset of patients, achieving the desired response rate for all remains an unmet clinical goal. Strategies that enhance responses to immune checkpoint blockade, including combining immunotherapy with chemotherapy, molecularly targeted therapy, or radiotherapy, may improve response rates and clinical outcomes. In this review, we provide a short background on TNBC and immunotherapy and explore the different types of immunotherapy strategies that are currently being evaluated in TNBC. Additionally, we review why combination strategies may be beneficial, provide an overview of the combination strategies, and discuss the novel immunotherapeutic opportunities that may be approved in the near future for TNBC.

Pancreatic cancer presents formidable challenges due to rapid progression and resistance to conventional treatments. Oncolytic viruses (OVs) selectively infect cancer cells and cause cancer cells to lyse, releasing molecules that can be identified by the host's immune system. Moreover, OV can carry immune-stimulatory payloads such as interleukin-12, which when delivered locally can enhance immune system-mediated tumor killing. OVs are very well tolerated by cancer patients due to their ability to selectively target tumors without affecting surrounding normal tissues. OVs have recently been combined with other therapies, including chemotherapy and immunotherapy, to improve clinical outcomes. Several OVs including adenovirus, herpes simplex viruses (HSVs), vaccinia virus, parvovirus, reovirus, and measles virus have been evaluated in preclinical and clinical settings for the treatment of pancreatic cancer. We evaluated the safety and tolerability of a replication-competent oncolytic adenoviral vector carrying two suicide genes (thymidine kinase, TK; and cytosine deaminase, CD) and human interleukin-12 (hIL12) in metastatic pancreatic cancer patients in a phase 1 trial. This vector was found to be safe and well-tolerated at the highest doses tested without causing any significant adverse events (SAEs). Moreover, long-term follow-up studies indicated an increase in the overall survival (OS) in subjects receiving the highest dose of the OV. Our encouraging long-term survival data provide hope for patients with advanced pancreatic cancer, a disease that has not seen a meaningful increase in OS in the last five decades. In this review article, we highlight several preclinical and clinical studies and discuss future directions for optimizing OV therapy in pancreatic cancer. We envision OV-based gene therapy to be a game changer in the near future with the advent of newer generation OVs that have higher specificity and selectivity combined with personalized treatment plans developed under AI guidance.

The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint constitutes an inhibitory pathway best known for its regulation of cluster of differentiation 8 (CD8)+ T cell-mediated immune responses. Engagement of PD-L1 with PD-1 expressed on CD8+ T cells activates downstream signaling pathways that culminate in T cell exhaustion and/or apoptosis. Physiologically, these immunosuppressive effects exist to prevent autoimmunity, but cancer cells exploit this pathway by overexpressing PD-L1 to facilitate immune escape. Intravenously (IV) administered immune checkpoint inhibitors (ICIs) that block the interaction between PD-1/PD-L1 have achieved great success in reversing T cell exhaustion and promoting tumor regression in various malignancies. However, these ICIs can cause immune-related adverse events (irAEs) due to off-tumor toxicities which limits their therapeutic potential. Therefore, considerable effort has been channeled into exploring alternative delivery strategies that enhance tumor-directed delivery of PD-1/PD-L1 ICIs and reduce irAEs. Here, we briefly describe PD-1/PD-L1-targeted cancer immunotherapy and associated irAEs. We then provide a detailed review of alternative delivery approaches, including locoregional (LDD)-, oncolytic virus (OV)-, nanoparticle (NP)-, and ultrasound and microbubble (USMB)-mediated delivery that are currently under investigation for enhancing tumor-specific delivery to minimize toxic off-tumor effects. We conclude with a commentary on key challenges associated with these delivery methods and potential strategies to mitigate them.

Due to the size and location of the tumor, incomplete radiofrequency ablation (iRFA) of the target tumor inhibits tumor immunity. In this study, a murine herpes simplex virus (oHSV2-mGM) armed with granulocyte-macrophage colony-stimulating factor (GM-CSF) was constructed to explore its effect on innate and adaptive immunity during iRFA, and the inhibitory effect of programmed cell death-1 (PD1) on tumor.

We verified the polarization and activation of RAW264.7 cells mediated by oHSV2-mGM in vitro. Subsequently, we evaluated the efficacy of oHSV2-mGM alone and in combination with αPD1 in the treatment of residual tumors after iRFA in two mouse models. RNA-seq was used to characterize the changes of tumor microenvironment.

oHSV2-mGM lysate effectively stimulated RAW264.7 cells to polarize into M1 cells and activated M1 phenotypic function. In the macrophage clearance experiment, oHSV2-mGM activated the immune response of tumor in mice. The results in vivo showed that oHSV2-mGM showed better anti-tumor effect in several mouse tumor models. Finally, oHSV2-mGM combined with PD1 antibody can further enhance the anti-tumor effect of oHSV2-mGM and improve the complete remission rate of tumor in mice.

The application of oHSV2-mGM leads to the profound remodeling of the immune microenvironment of residual tumors. oHSV2-mGM also works in synergy with PD1 antibody to achieve complete remission of tumors that do not respond well to monotherapy at immune checkpoints. Our results support the feasibility of recombinant oncolytic virus in the treatment of residual tumors after iRFA, and propose a new strategy for oncolytic virus treatment of tumors.

Proliferating cell nuclear antigen (PCNA) is a well-documented accessory protein of DNA repair and replication. It belongs to the sliding clamp family of proteins that encircle DNA and acts as a mobile docking platform for interacting proteins to mount and perform their metabolic tasks. PCNA presence is ubiquitous to all cells, and when located in the nucleus it plays a role in DNA replication and repair, cell cycle control and apoptosis in proliferating cells. It also plays a crucial role in the infectivity of some viruses, such as herpes simplex viruses (HSVs). However, more recently it has been found in the cytoplasm of immune cells such as neutrophils and macrophages where it has been shown to be involved in the development of a pro-inflammatory state. PCNA is also expressed on the surface of certain cancer cells and can play a role in preventing immune cells from killing tumours, as well as being associated with cancer virulence. Given the growing interest in oncolytic viruses (OVs) as a novel cancer therapeutic, this review considers the role of PCNA in healthy, cancerous, and immune cells to gain an understanding of how PCNA targeted therapy and oncolytic virotherapy may interact in the future.

Cancer immunotherapy has sparked a wave of cancer research, driven by recent successful proof-of-concept clinical trials. However, barriers are emerging during its rapid development, including broad adverse effects, a lack of reliable biomarkers, tumor relapses, and drug resistance. Integration of nanomedicine may ameliorate current cancer immunotherapy. Ultra-large surface-to-volume ratio, extremely small size, and easy modification surface of nanoparticles enable them to selectively detect cells and kill cancer cells in vivo. Exciting synergistic applications of the two approaches have emerged in treating various cancers at the intersection of cancer immunotherapy and cancer nanomedicine, indicating the potential that the combination of these two therapeutic modalities can lead to new paradigms in the treatment of cancer. This review discusses the status of current immunotherapy and explores the possible opportunities that the nanomedicine platform can make cancer immunotherapy more powerful and precise by synergizing the two approaches.

Nanovaccines have been designed to overcome the limitations associated with conventional vaccines. Effective delivery methods such as engineered carriers or smart nanoparticles (NPs) are critical requisites for inducing self-tolerance and optimizing vaccine immunogenicity with minimum side effects. NPs can be used as adjuvants, immunogens, or nanocarriers to develop nanovaccines for efficient antigen delivery. Multiloaded nanovaccines carrying multiple tumor antigens along with immunostimulants can effectively increase immunity against tumor cells. They can be biologically engineered to boost interactions with dendritic cells and to allow a gradual and constant antigen release. Modifying NPs surface properties, using high-density lipoprotein-mimicking nanodiscs, and developing nano-based artificial antigen-presenting cells such as dendritic cell-derived-exosomes are amongst the new developed technologies to enhance antigen-presentation and immune reactions against tumor cells. The present review provides an overview on the different perspectives, improvements, and barriers of successful clinical application of current cancer therapeutic and vaccination options. The immunomodulatory effects of different types of nanovaccines and the nanoparticles incorporated into their structure are described. The advantages of using nanovaccines to prevent and treat common illnesses such as AIDS, malaria, cancer and tuberculosis are discussed. Further, potential paths to develop optimal cancer vaccines are described. Given the immunosuppressive characteristics of both cancer cells and the tumor microenvironment, applying immunomodulators and immune checkpoint inhibitors in combination with other conventional anticancer therapies are necessary to boost the effectiveness of the immune response.

Pancreatic adenocarcinoma, a clinically challenging malignancy constitutes a significant contributor to cancer-related mortality, characterized by an inherently poor prognosis. This review aims to provide a comprehensive understanding of pancreatic adenocarcinoma by examining its multifaceted etiologies, including genetic mutations and environmental factors. The review explains the complex molecular mechanisms underlying its pathogenesis and summarizes current therapeutic strategies, including surgery, chemotherapy, and emerging modalities such as immunotherapy. Critical molecular pathways driving pancreatic cancer development, including KRAS, Notch, and Hedgehog, are discussed. Current therapeutic strategies, including surgery, chemotherapy, and radiation, are discussed, with an emphasis on their limitations, particularly in terms of postoperative relapse. Promising research areas, including liquid biopsies, personalized medicine, and gene editing, are explored, demonstrating the significant potential for enhancing diagnosis and treatment. While immunotherapy presents promising prospects, it faces challenges related to immune evasion mechanisms. Emerging research directions, encompassing liquid biopsies, personalized medicine, CRISPR/Cas9 genome editing, and computational intelligence applications, hold promise for refining diagnostic approaches and therapeutic interventions. By integrating insights from genetic, molecular, and clinical research, innovative strategies that improve patient outcomes can be developed. Ongoing research in these emerging fields holds significant promise for advancing the diagnosis and treatment of this formidable malignancy.

Hepatocellular carcinoma (HCC) is a systemic disease with augmented malignant degree, high mortality and poor prognosis. Since the establishment of the immune mechanism of tumor therapy, people have realized that immunotherapy is an effective means for improvement of HCC patient prognosis. Oncolytic virus is a novel immunotherapy drug, which kills tumor cells and exempts normal cells by directly lysing tumor and inducing anti-tumor immune response, and it has been extensively examined as an HCC therapy. This editorial discusses oncolytic viruses for the treatment of HCC, emphasizing viral immunotherapy strategies and clinical applications related to HCC.

Recent studies have indicated that combining oncolytic viruses with CAR-T cells in therapy has shown superior anti-tumor effects, representing a promising approach. Nonetheless, the localized delivery method of intratumoral injection poses challenges for treating metastatic tumors or distal tumors that are difficult to reach. To address this obstacle, we employed HSV-1-infected CAR-T cells, which systemically delivery HSV into solid tumors. The biological function of CAR-T cells remained intact after loading them with HSV for a period of three days. In both immunocompromised and immunocompetent GBM orthotopic mouse models, B7-H3 CAR-T cells effectively delivered HSV to tumor lesions, resulting in enhanced T-cell infiltration and significantly prolonged survival in mice. We also employed a bilateral subcutaneous tumor model and observed that the group receiving intratumoral virus injection exhibited a significant reduction in tumor volume on the injected side, while the group receiving intravenous infusion of CAR-T cells carrying HSV displayed suppressed tumor growth on both sides. Hence, CAR-THSV cells offer notable advantages in the systemic delivery of HSV to distant tumors. In conclusion, our findings emphasize the potential of CAR-T cells as carriers for HSV, presenting significant advantages for oncolytic virotherapy targeting distant tumors.

Adenoviral vectors are crucial for gene therapy and vaccine development, offering a platform for gene delivery into host cells. Since the discovery of adenoviruses, first-generation vectors with limited capacity have evolved to third-generation vectors flacking viral coding sequences, balancing safety and gene-carrying capacity. The applications of adenoviral vectors for gene therapy and anti-viral treatments have expanded through the use of in vitro ligation and homologous recombination, along with gene editing advancements such as CRISPR-Cas9. Current research aims to maintain the efficacy and safety of adenoviral vectors by addressing challenges such as pre-existing immunity against adenoviral vectors and developing new adenoviral vectors from rare adenovirus types and non-human species. In summary, adenoviral vectors have great potential in gene therapy and vaccine development. Through continuous research and technological advancements, these vectors are expected to lead to the development of safer and more effective treatments.

Cancer is a significant global health issue that poses a considerable burden on both patients and healthcare systems. Many different types of cancers exist that often require unique treatment approaches and therapies. A hallmark of tumor progression is the creation of an immunosuppressive environment, which poses complex challenges for current treatments. Amongst the most explored characteristics is a hypoxic environment, high interstitial pressure, and immunosuppressive cells and cytokines. Traditional cancer treatments involve radiotherapy, chemotherapy, and surgical procedures. The advent of immunotherapies was regarded as a promising approach with hopes of greatly increasing patients' survival and outcome. Although some success is seen with various immunotherapies, the vast majority of monotherapies are unsuccessful. This review examines how various aspects of the tumor microenvironment (TME) present challenges that impede the success of immunotherapies. Subsequently, we review strategies to manipulate the TME to facilitate the success of immunotherapies.

Mesenchymal stem/stromal cells (MSCs) are one of the most widely used cell types in advanced therapies due to their therapeutic potential in the regulation of tissue repair and homeostasis, and immune modulation. However, their use in cancer therapy is controversial: they can inhibit cancer cell proliferation, but also potentially promote tumour growth by supporting angiogenesis, modulation of the immune milieu and increasing cancer stem cell invasiveness. This opposite behaviour highlights the need for careful and nuanced use of MSCs in cancer treatment. To optimize their anti-cancer effects, diverse strategies have bioengineered MSCs to enhance their tumour targeting and therapeutic properties or to deliver anti-cancer drugs. In this review, we highlight the advanced uses of MSCs in cancer therapy, particularly as carriers of targeted treatments due to their natural tumour-homing capabilities. We also discuss the potential of MSC-derived extracellular vesicles to improve the efficiency of drug or molecule delivery to cancer cells. Ongoing clinical trials are evaluating the therapeutic potential of these cells and setting the stage for future advances in MSC-based cancer treatment. It is critical to identify the broad and potent applications of bioengineered MSCs in solid tumour targeting and anti-cancer agent delivery to position them as effective therapeutics in the evolving field of cancer therapy.

V937 is an investigational, genetically unmodified Kuykendall strain of coxsackievirus A21, which has been evaluated in the clinic for advanced solid tumor malignancies. V937 specifically infects and lyses tumor cells that overexpress intercellular adhesion molecule-1 (ICAM-1). Intratumoral V937 as a monotherapy and in combination with anti-PD-1 antibody pembrolizumab has shown clinical response in patients with metastatic melanoma, which overexpresses ICAM-1. Here, we investigate in preclinical studies the potential bidirectional cross-talk between hepatocellular carcinomas (HCC) or colorectal carcinomas (CRC) and immune cells when treated with V937 alone or in combination with pembrolizumab. We show that while V937 treatment of tumor cell lines or organoids or peripheral blood mononuclear cells (PBMCs) alone induced a minimal immunological response, V937 treatment of non-contact co-cultures of tumor cell lines or CRC organoids with PBMCs led to robust production of proinflammatory cytokines and immune cell activation. In addition, both recombinant interferon-gamma and pembrolizumab increased ICAM-1 on tumor cell lines or organoids and, in turn, amplified V937-mediated oncolysis and immunogenicity. These findings provide critical mechanistic insights on the cross-talk between V937-mediated oncolysis and immune responses, demonstrating the therapeutic potential of V937 in combination with PD-1 blockade to treat immunologically quiescent cancers.

Managing malignant brain tumors remains a significant therapeutic hurdle that necessitates further research to comprehend their treatment potential fully. Oncolytic viruses (OVs) offer many opportunities for predicting and combating tumors through several mechanisms, with both preclinical and clinical studies demonstrating potential. OV therapy has emerged as a potent and effective method with a dual mechanism. Developing innovative and effective strategies for virus transduction, coupled with immune checkpoint inhibitors or chemotherapy drugs, strengthens this new technique. Furthermore, the discovery and creation of new OVs that can seamlessly integrate gene therapy strategies, such as cytotoxic, anti-angiogenic, and immunostimulatory, are promising advancements. This review presents an overview of the latest advancements in OVs transduction for brain cancer, focusing on the safety and effectiveness of G207, G47Δ, M032, rQNestin34.5v.2, C134, DNX-2401, Ad-TD-nsIL12, NSC-CRAd-S-p7, TG6002, and PVSRIPO. These are evaluated in both preclinical and clinical models of various brain tumors.

Antitumor therapies based on adoptively transferred T cells or oncolytic viruses have made significant progress in recent years, but the limited efficiency of their infiltration into solid tumors makes it difficult to achieve desired antitumor effects when used alone. In this study, an oncolytic virus (rVSV-LCMVG) that is not prone to induce virus-neutralizing antibodies was designed and combined with adoptively transferred T cells. By transforming the immunosuppressive tumor microenvironment into an immunosensitive one, in B16 tumor-bearing mice, combination therapy showed superior antitumor effects than monotherapy. This occurred whether the OV was administered intratumorally or intravenously. Combination therapy significantly increased cytokine and chemokine levels within tumors and recruited CD8+ T cells to the TME to trigger antitumor immune responses. Pretreatment with adoptively transferred T cells and subsequent oncolytic virotherapy sensitizes refractory tumors by boosting T-cell recruitment, down-regulating the expression of PD-1, and restoring effector T-cell function. To offer a combination therapy with greater translational value, mRNA vaccines were introduced to induce tumor-specific T cells instead of adoptively transferred T cells. The combination of OVs and mRNA vaccine also displays a significant reduction in tumor burden and prolonged survival. This study proposed a rational combination therapy of OVs with adoptive T-cell transfer or mRNA vaccines encoding tumor-associated antigens, in terms of synergistic efficacy and mechanism.

Enhanced cellular therapy has emerged as a novel concept following the basis of cellular therapy. This treatment modality applied drugs or biotechnology to directly enhance or genetically modify cells to enhance the efficacy of adoptive cellular therapy (ACT). Drugs or biotechnology that enhance the killing ability of immune cells include immune checkpoint inhibitors (ICIs) / antibody drugs, small molecule inhibitors, immunomodulatory factors, proteolysis targeting chimera (PROTAC), oncolytic virus (OV), etc. Firstly, overcoming the inhibitory tumor microenvironment (TME) can enhance the efficacy of ACT, which can be achieved by blocking the immune checkpoint. Secondly, cytokines or cytokine receptors can be expressed by genetic engineering or added directly to adoptive cells to enhance the migration and infiltration of adoptive cells to tumor cells. Moreover, multi-antigen chimeric antigen receptors (CARs) can be designed to enhance the specific recognition of tumor cell-related antigens, and OVs can also stimulate antigen release. In addition to inserting suicide genes into adoptive cells, PROTAC technology can be used as a safety switch or degradation agent of immunosuppressive factors to enhance the safety and efficacy of adoptive cells. This article comprehensively summarizes the mechanism, current situation, and clinical application of enhanced cellular therapy, describing potential improvements to adoptive cellular therapy.