RNA modifications are crucial for post-transcriptional gene regulation. Research on RNA modifications has become a novel frontier of epitranscriptomics. Up to now, over 170 kinds of modifications have been identified on mRNA and diverse non-coding RNA. Three classes of proteins (writers, erasers, and readers) regulate the addition, removal, and identification of epigenetic marks, thus affecting RNA biological functions. Increasing evidence identifies the dysregulation of RNA modifications in different cancer types and the therapeutic potential of targeting RNA-modifying enzymes. The ability of RNA modifications to improve mRNA stability and translation efficacy and decrease immunogenicity has been exploited for the clinical use of mRNA cancer vaccines. This review aims to shed light on several vital cap, tail, and internal modifications of RNA with a focus on the connection between RNA epigenetic pathways and cancer pathogenesis. We further explore the clinical potential of RNA modifications as dynamic biomarkers for cancer diagnosis, prognosis, and therapeutic response prediction, addressing both technological challenges and translational opportunities. Finally, we analyze the limitations of current studies and discuss the research focus in the future.

OVV-01 is a genetically engineered vesicular stomatitis virus oncolytic virus designed to selectively amplify in tumor cells and express tumor-associated antigen NY-ESO-1. This study was designed to evaluate the safety, tolerability, and efficacy of OVV-01 in patients with advanced solid tumors.

This is a phase 1, first-in-human, open-label, multicenter study of OVV-01 in patients with advanced solid tumors. OVV-01 was intratumorally injected biweekly (every two weeks, Q2W), 3 weeks after the first dose for a total of six doses. Dose escalation follows a 3+3 design at four doses of 6×107 Plaue-Forming Unit (PFU), 6×108 PFU, 6×109 PFU, and 1.2×1011 PFU. The primary endpoints were safety and tolerability. The second endpoints included overall response rate (ORR) and disease control rate (DCR) of OVV-01, by investigators per Response Evaluation Criteria in Solid Tumors V.1.1.

18 patients were enrolled into four dose groups, among whom 6 were soft tissue sarcoma (STS). No dose-limiting toxicities and treatment-related severe adverse events were observed. 11 patients were evaluated for efficacy, and the ORR was 27.3%, and the DCR was 63.6%. Among the four evaluable patients with advanced STS, the ORR was 75%. Two patients with STS achieved CR at doses above 6.0×109 PFU.

The intratumor injection of OVV-01 was safe and well-tolerated in patients with advanced solid tumors. A significant response was observed in patients with STS.

NCT04787003.

Melanoma is the most dangerous skin cancer due to its difficulty in treatment, high recurrence rate and metastatic ability. As a vector for oncolytic viruses (OVs), vesicular stomatitis virus (VSV) has been shown to be effective against malignant melanoma. However, the glycoprotein G protein of VSV has potential neurotoxicity. It has been shown that replacing glycoprotein G with E3-E2-6K-E1 of chikungunya virus (CHIKV) reduces its neurotoxicity and targets gliomas. Therefore, the aim of this study was to investigate the oncolytic effect of recombinant VSV-CHIKV on melanoma and the underlying mechanism. In this study, we found that recombinant VSV-CHIKV triggered GSDMD-mediated melanoma cell pyroptosis. Importantly, the NLRP3/Caspase-1/GSDMD axis was activated after VSV-CHIKV infection in melanoma cell lines and in a xenograft mouse model. Inhibition of GSDMD blocked cell pyroptosis, antitumor immunity and the tumor response in response to VSV-CHIKV treatment, suggesting that VSV-CHIKV act through the GSDMD pathway. VSV-CHIKV-triggered GSDMD-mediated tumor pyroptosis recruited cytotoxic T lymphocytes (CTLs) into the tumor microenvironment, which was accompanied by the release of inflammatory mediators. This remodeled the tumor microenvironment and turned immunologically "cold" tumors into "hot" tumors, thereby sensitized these tumors to checkpoint blockade. Finally, the combination therapy of VSV-CHIKV and an immune checkpoint inhibitor (anti-PD-1) prolonged the survival of mice. In conclusion, the VSV-CHIKV strategy is an attractive biologic therapy against melanoma.

Urologic tumors are among the most common malignancies worldwide, and the association between chronic infections and the risk of developing these tumors has garnered significant attention. However, traditional observational studies are prone to confounding factors, making it challenging to establish a clear causal relationship.

This study employs a two-sample bidirectional Mendelian randomization analysis, utilizing genetic data on antibody levels and urologic tumors obtained from GWAS databases. The inverse variance weighted (IVW) method was used to estimate causal relationships, while MR-Egger and MR-PRESSO methods were applied for sensitivity analyses to assess horizontal pleiotropy and heterogeneity.

The results showed that antibody levels associated with various viral infections were significantly correlated with the risk of developing urologic tumors. For example, antibodies related to cytomegalovirus IgG and Epstein-Barr virus (EBV) were found to have complex associations with the risk of prostate cancer, bladder cancer, and testicular cancer. Some antibodies, such as those related to Varicella zoster virus, were associated with a reduced risk of clear cell renal carcinoma. Additionally, sensitivity analyses suggested the potential presence of horizontal pleiotropy in bladder and testicular cancers.

Through Mendelian randomization analysis, we revealed a potential causal relationship between antibody immune responses and urologic tumors. These findings provide new evidence for the role of chronic infections in the pathogenesis of urologic tumors, suggesting that prevention and treatment strategies targeting related pathogens, such as vaccination and antiviral therapies, could offer new avenues for the prevention and management of urologic cancers.

Cytoplasmic pattern recognition receptors (PRR) for double-stranded RNA, such as RIG-I/MDA5, are key mediators of anti-viral responses. Here we screen for synergistic drug-virotherapy combinations and find that the reovirus type III Dearing strain (Rt3D)-palbociclib combination augments oncolytic virus-induced stress responses and increases interferon production and signaling. Data from RIG-I agonist and ER stress-inducing agents further confirms the crosstalk between RNA-sensing and ER stress in inducing cancer cell death and interferon production. Combined Rt3D-palbociclib also increases innate immune activation and IFN-induced HLA expression within tumor cells, with accompanying alterations in the epigenetic landscape and endogenous retroviral (ERV) elements. Analysis of the immunopeptidome in treated cells further reveals changes to HLA-captured peptides, including altered expression of peptides from cancer or testis antigens and ERVs. Our findings thus highlight the crosstalk between stress signaling and PRR activation for mediating enhanced anti-cancer efficacy.

Heterologous oncolytic virus prime-boost vaccination is emerging as a promising cancer immunotherapy to establish potent antitumor immunity. With their natural ability to specifically destroy cancer cells, oncolytic viruses also allow for direct oncolysis and our team has previously demonstrated that they can be used as vaccination adjuvants when co-administered with antigenic peptides. As such, adjuvant oncolytic virus vaccines can easily be tailored to target any antigen, which is particularly important in the context of personalized vaccines against patient-specific mutations. Here, we tested if oncolytic viruses engineered to express the immune-stimulating transgene interleukin-2 have improved vaccination adjuvant potential.

For this proof-of-concept study, we generated an oncolytic vesicular stomatitis virus (VSV) variant (MD51) that encodes the T-cell activator cytokine interleukin-2 and measured its vaccination adjuvant potential in a heterologous virus immune boosting approach, 1 week after immune priming compared with the parental virus (also MD51). Tumor-free and B16F10-Ova tumor-bearing mice were vaccinated against the Ova peptide using either virus as adjuvants. The immune response induced by each vaccination regimen was assessed by flow cytometry to characterize antigen-specific CD8 T cells over time. Treatment efficacy was also measured.

Our data show that VSV-interleukin-2 is superior as a vaccine boosting adjuvant compared with the parental virus as it induces more antigen-specific CD8 T cells with enhanced effector functions that persist over time. VSV-interleukin-2 vaccination also improves tumor control and survival.

Overall, we show that engineered oncolytic virus platforms, such as VSV-interleukin-2, have the potential to improve vaccination efficacy and treatment outcomes. Our findings deepen our understanding of the immune mechanisms underlying the use of oncolytic viruses as anticancer vaccination platforms and will allow for the development of a new generation of improved oncolytic virus vaccine adjuvants.

NCT02285816.

Resistance to radiotherapy is a significant challenge in the clinical management of non-small cell lung cancer (NSCLC). This study investigates a novel multimodal therapeutic strategy that combines oncolytic Newcastle disease virus (NDV) with an anti-VEGFR2 single-chain variable fragment (NDV-anti-VEGFR2) to enhance radiosensitivity in NSCLC. We engineered NDV-anti-VEGFR2 and assessed its efficacy in sensitizing Calu-1 cells to radiation. In vitro results demonstrated that NDV-anti-VEGFR2 significantly inhibited tumor cell proliferation when combined with radiotherapy. In vivo experiments revealed that NDV-anti-VEGFR2, combined with radiation, achieved a tumor growth inhibition rate of 86.48%, surpassing the effects of NDV or radiation alone. Mechanistic investigations indicated that NDV-anti-VEGFR2 mitigated hypoxia by downregulating HIF-1α and impaired DNA repair pathways, as evidenced by reduced levels of RAD51 and γ-H2AX. These findings suggest that NDV-anti-VEGFR2 not only normalizes tumor vasculature but also enhances the cytotoxic effects of radiation by compromising DNA repair mechanisms. Collectively, our results support the clinical potential of NDV-anti-VEGFR2 combined with radiotherapy as a promising strategy to overcome radiotherapy resistance in NSCLC. Future studies in immunocompetent models are warranted to elucidate the immune-mediated effects of this innovative therapeutic approach.

Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to its immunosuppressive tumor microenvironment (TME). Oncolytic herpes simplex virus type 1 (oHSV1) offers dual mechanisms of tumor lysis and immune activation, yet the optimal cytokine payloads for TNBC remain undefined.

We developed a CRISPR/Cas9-mediated platform for high-efficiency oHSV1 engineering, replacing the ICP47 locus with murine IFN-γ, GM-CSF, or IL-15Rα/IL-15 fusion protein (IL15Fu). Constructs were validated for cytokine secretion, MHC modulation, and cytotoxicity in 4T1 TNBC and a panel of human cancer cell lines. Antitumor efficacy and immune remodeling were evaluated in a syngeneic 4T1 model using RNA sequencing and flow cytometry.

The CRISPR platform achieved 62.5-71.4% homologous recombination efficiency, enabling rapid virus construction. In vitro, OV-IFNG exhibited upregulated MHC I/II expression and potent cytotoxicity, while OV-GMCSF attenuated oncolysis in subsets of breast cancer cell lines. In the 4T1 model, OV-IL15Fu modestly improved tumor control and extended survival without apparent toxicity, while OV-IFNG induced early mortality associated with systemic toxicity. Transcriptomic profiling revealed divergent immune modulation: OV-IL15Fu enriched T cell/NK cytotoxicity pathways, OV-IFNG amplified cytokine/chemokine signaling, and OV-GMCSF paradoxically enhanced myeloid recruitment while inhibiting MHC-II pathways. Flow cytometry confirmed functional differences in immune activation: OV-IL15Fu expanding cytotoxic lymphocytes (CD8⁺ T/NK cells), OV-IFNG preferentially promote Th1 polarization and innate immune activation, and OV-GMCSF failed to activate T cells despite myeloid infiltration.

Our findings underscore the need for rational cytokine selection in oHSV1-based immunotherapy. While IFN-γ increased immunogenic markers, its systemic toxicity and myeloid effects may limit benefit. GM-CSF exacerbated immune suppression in this context, whereas IL15Fu showed favorable immunostimulatory properties without detectable toxicity. These data support IL15Fu as a contextually promising payload for further evaluation in TNBC-targeted oncolytic virotherapy.

Oncolytic viruses (OVs) are a promising class of cancer therapy, exploiting their abilities to selectively infect and kill cancer cells while stimulating antitumor immune responses. The current assessment explores the changing horizons of OV immunotherapy, focusing on recent advances in technology plans to improve OV projects and combined approaches to improve curative efficacy. We discuss how OVs induce direct oncolysis and promote the release of tumor-associated antigens, leading to the activation of both innate and adaptive immunity. Special attention shall be given to programs for arm OVs to express curative genes, modify the tumor microenvironment and overcome immunosuppression. Moreover, we assess the synergies of uniting OVs with other immunotherapeutic techniques, such as immune checkpoint inhibitors and cell therapy, to improve tolerant outcomes. The present assessment provides an understanding of the relevant declaration of the OV analysis, highlighting the main obstacles and the future directions for the development of other capable and targeted cancer immunotherapy.

Oncolytic viruses (OVs) represent a promising experimental therapy for a range of cancers, including oral squamous cell carcinoma (OSCC). In this study, oHSV refers to an oncolytic virus engineered from HSV-1(Herpes Simplex Virus Type 1). The oHSV-1 is an oncolytic virus derived from HSV-1, where both copies of the ICP34.5 coding sequences have been replaced with the EGFP gene, and the ICP47 gene has been deleted. In previous studies, resistance was observed in certain SCC15 xenograft models treated with oncolytic herpes simplex viruses (oHSV-1). Primary tumor cells were extracted from these resistant models, followed by RNA sequencing with SCC15 cells as controls. Analysis revealed that ISG15 expression was upregulated in the resistant primary cells, as well as in HSV-infected breast cancer cells (GSE137757). In this study, we confirmed that knockdown ISG15 in SCC15 cells enhanced oHSV-1 replication, while ISG15 overexpression suppressed it. Mechanistic studies demonstrated that ISG15 inhibits oHSV-1 replication via ISGylation. To improve the therapeutic efficacy of oHSV-1, an oHSV-1 variant expressing ISG15-targeting short hairpin RNA (shRNA), termed oHSV-1-shISG15, was engineered. oHSV-1-shISG15 exhibited enhanced antitumor efficacy compared to oHSV-1 in vitro and in vivo. These findings suggest that ISG15 depletion augments oHSV-1 replication in OSCC tumor cells through ISGylation inhibition. Meanwhile, this study provides a novel recombinant oncolytic virus to potentiate the efficacy of oncolytic herpes virotherapy.

Effective cancer therapy involves initiation of a tumor-specific immune response. Consequently, the interest in oncolytic viruses (OV) capable of triggering immunogenic cell death has sparked in recent years. However, the common use of pre-clinical models that fail to mirror patient tumor ecosystems (TES) hinders clinical translation. Here, we provide a condensed view on the intricate interplay between several aspects of TES and OV action and discuss these considerations in the view of recently developed pre-clinical human model systems. Given the urgent demand for innovative cancer treatments, the purpose of this review is to highlight the so-far overlooked complex impact of the tumor microenvironment (TME) on OV permissivity, with the intent to provide a foundation for future, more effective pre-clinical studies.

Immunotherapy has transformed the landscape of cancer treatment, with T cell-based strategies at the forefront of this revolution. However, the durability of these responses is frequently undermined by two intertwined phenomena: T cell exhaustion and senescence. While exhaustion is driven by chronic antigen exposure in the immunosuppressive tumor microenvironment, leading to a reversible state of diminished functionality, senescence reflects a more permanent, age- or stress-induced arrest in cellular proliferation and effector capacity. Together, these processes represent formidable barriers to sustained anti-tumor immunity. In this review, we dissect the molecular underpinnings of T cell exhaustion and senescence, revealing how these dysfunctions synergistically contribute to immune evasion and resistance across a range of solid tumors. We explore cutting-edge therapeutic approaches aimed at rewiring the exhausted and senescent T cell phenotypes. These include advances in immune checkpoint blockade, the engineering of "armored" CAR-T cells, senolytic therapies that selectively eliminate senescent cells, and novel interventions that reinvigorate the immune system's capacity for tumor eradication. By spotlighting emerging strategies that target both exhaustion and senescence, we provide a forward-looking perspective on the potential to harness immune rejuvenation. This comprehensive review outlines the next frontier in cancer immunotherapy: unlocking durable responses by overcoming the immune system's intrinsic aging and exhaustion, ultimately paving the way for transformative therapeutic breakthroughs.

Neoantigen-based immunotherapy has emerged as a transformative approach in cancer treatment, offering precision medicine strategies that target tumor-specific antigens derived from genetic, transcriptomic, and proteomic alterations unique to cancer cells. These neoantigens serve as highly specific targets for personalized therapies, promising more effective and tailored treatments. The aim of this article is to explore the advances in neoantigen-based therapies, highlighting successful treatments such as vaccines, tumor-infiltrating lymphocyte (TIL) therapy, T-cell receptor-engineered T cells therapy (TCR-T), and chimeric antigen receptor T cells therapy (CAR-T), particularly in cancer types like glioblastoma (GBM). Advances in technologies such as next-generation sequencing, RNA-based platforms, and CRISPR gene editing have accelerated the identification and validation of neoantigens, moving them closer to clinical application. Despite promising results, challenges such as tumor heterogeneity, immune evasion, and resistance mechanisms persist. The integration of AI-driven tools and multi-omic data has refined neoantigen discovery, while combination therapies are being developed to address issues like immune suppression and scalability. Additionally, the article discusses the ongoing development of personalized immunotherapies targeting tumor mutations, emphasizing the need for continued collaboration between computational and experimental approaches. Ultimately, the integration of cutting-edge technologies in neoantigen research holds the potential to revolutionize cancer care, offering hope for more effective and targeted treatments.

Oncolytic viruses (OVs) are natural or recombinant viruses that can directly lyse tumor cells without damaging normal cells. They enhance anti-tumor immunity by releasing antigens and activating inflammatory responses within the tumor microenvironment (TME). This offers a new therapeutic approach for MPE and solid tumors. This review discusses the progress of OVs administered via intrapleural and intratumoral routes, emphasizing their potential in MPE treatment and the challenges posed by the complex intrapleural environment, which affects the direct interaction between OVs, tumor cells, and immune cells. This review also discusses the regulatory barriers, safety concerns and accessibility of oncolytic virus therapy.

Breast cancer remains the most frequently diagnosed cancer and the second highest cause of cancer death in females. Metastatic recurrence that is resistant to traditional therapies presents a major challenge, necessitating the development of an innovative treatment strategy. Immunotherapy has gained popularity in the treatment of cancer, particularly melanoma, lung cancer, and more recently breast cancer. Major developments in immunotherapy have been made with a better understanding of the tumor microenvironment and how the microenvironment can be manipulated to induce an anti-tumor immune response. Intratumorally delivered immunotherapy can be used to create a local immune response. This review provides a comprehensive overview of intratumoral immunotherapy for breast cancer and its resultant changes in the tumor microenvironment. The discussed immunotherapeutics include oncolytic viruses, nucleic acids, innate immune agonists, bacteria, chimeric antigen receptor T cells, and dendritic cells. The review also evaluates completed clinical trials using these therapies. Lastly, the review offers future perspectives in the development of breast cancer immunotherapy.

Oncolytic herpes simplex virus (oHSV) represents a promising therapeutic approach to treating cancers by virtue of its selective replication in and lysis of tumor cells, with stimulation of host antitumor immunity. At present, four OV drugs have been approved for the treatment of cancers worldwide, two of which are oHSV drugs that have received extensive attention, known as T-VEC and Delytact. This review discusses the history, mechanism of action, clinical development, quality control, and evaluation principles of oHSV products, including viral species and genetic modifications that have improved these products' therapeutic potential, limitations, and future directions. Integration of oHSVs with immunotherapeutic agents and conventional therapies has a promising future in the field of treatment of malignant tumors. Although much progress has been achieved, there is still much work to be done regarding the optimization of treatment protocols and the quality control of oncolytic virus drugs. The approval of various oncolytic virus therapies underlines their clinical relevance, safety, and efficacy, thereby paving the way for further research aimed at overcoming the existing limitations and enhancing patient responses.

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.

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.

Lung cancer is the leading cause of cancer-related death globally. Despite various treatment options, adverse reactions and treatment resistance limit their clinical application and efficacy, therefore, new effective treatment options are still needed. Oncolytic viruses (OVs) are a new anti-cancer option. With a powerful anti-tumor effect, OVs are gradually being applied to the treatment of solid tumor. In clinical practice, we have found that in patients with NSCLC and SCLC, OVs combined with immune checkpoint inhibitors (ICI) treatment make tumor with poor response to immunotherapy become sensitive. Furthermore, studies have shown that OVs combined with chemotherapy, radiation therapy, and other immune approaches (such as anti-pd1 drugs) have synergistic effects. These studies suggest that OVs combined therapy may bring hope for the treatment of lung cancer patients. This article will review the current status and prospect of OVs combination therapy in the field of lung cancer treatment and summarizes the mechanism of action.

Oncolytic herpes simplex viruses (oHSV) preferentially replicate in cancer cells while inducing antitumor immunity, and thus, they are often referred to as in situ cancer vaccines. OHSV infection of tumors elicits diverse host immune responses comprising both innate and adaptive components. Although the innate and adaptive immune responses primarily target the tumor, they also contribute to antiviral immunity, limiting viral replication/oncolysis. OHSV-encoded proteins use various mechanisms to evade host antiviral pathways and immune recognition, favoring oHSV replication, oncolysis, and spread. In general, oHSV infection and replication within tumors results in a series of sequential events, such as oncolysis and release of tumor and viral antigens, dendritic cell-mediated antigen presentation, T cell priming and activation, T cell trafficking and infiltration to tumors, and T cell recognition of cancer cells, leading to tumor (and viral) clearance. These sequential events align with all steps of the cancer-immunity cycle. However, a comprehensive understanding of the interplay between oHSV and host immune responses is crucial to optimize oHSV-induced antitumor immunity and efficacy. Therefore, this review aims to elucidate oHSV's communication with innate and adaptive immune systems and use such interactions to improve oHSV's potential as a potent immunovirotherapeutic agent against cancer.

The anti-cancer mechanism of High-dose Vitamin C (HDVC) is mainly to participate in the Fenton reaction, hydroxylation reaction, and epigenetic modification, which leads to the energy crisis, metabolic collapse, and severe peroxidation stress that results in the proliferation inhibition or death of cancer cells. However, the mainstream view is that HDVC does not significantly improve cancer treatment outcomes. In clinical work and scientific research, we found that some drugs or therapies can significantly improve the anti-cancer effects of HDVC, such as PD-1 inhibitors that can increase the anti-cancer effects of cancerous HDVC by nearly three times. Here, the adjuvant and intensive therapy and synergistic mechanisms including HDVC combined application of chemoradiotherapies multi-vitamins, targeted drugs, immunotherapies, and oncolytic virus are discussed in detail. Adjuvant and intensive therapy of HDVC can significantly improve the therapeutic effect of HDVC in the metabolic treatment of cancer, but more clinical evidence is needed to support its clinical application.

Appropriate assessment of disease burden in patients with peritoneal surface malignancy (PSM) is critical for treatment decision-making, and conventional cross-sectional imaging (computed tomography and/or MRI) often underestimates burden of disease. Advances in imaging for PSM include novel functional imaging modalities that target cells unique to the tumor microenvironment. Novel alternative methods of diagnosis and disease monitoring are also potentially applicable to management of PSM. These include forms of "liquid biopsy" targeting circulating tumor DNA. Novel regional therapies include both new therapeutic agents (immune-based and nanoparticle-based), as well as new methods of delivery such as pressurized intraperitoneal aerosolized chemotherapy.

Over the past decade, the failure of multiple clinical trials has confirmed the need for a systematic and comprehensive understanding of glioblastoma (GBM). Current immunotherapies aiming to harness the immune system to achieve anti-tumor effects remain largely ineffective, highlighting the complexities of the GBM microenvironment. However, our recent understanding of immune niches within the central nervous system provides both opportunities and challenges in translating these insights into successful immunotherapy implementation. We discuss these strategies, including targeting multiple antigens within the heterogeneous GBM microenvironment, identifying new druggable targets to abrogate immunosuppression, and understanding niche-specific immune cell functionality to modulate tumor-immune-stroma interactions.

Newcastle disease virus (NDV) has shown encouraging effectiveness in in vitro, in vivo, and in early clinical trials as a viro-immunotherapy for pancreatic cancer. Previously, NDV used in clinical trials was produced in embryonated chicken eggs; however, egg-produced viruses are known to be partly neutralized by the human complement system when administered intravenously. Here, an NDV variant (NDV F0) was generated for production in mammalian cells, without passage in eggs. This was achieved by introducing the V-106-M and L-117-S amino acid substitutions upstream of the cleavage site in the F protein, resulting in rNDV F0-M, rNDV F0-S, and NDV F0-M/S. These viruses can be considered non-virulent as determined with in vivo pathogenicity testing and were neutralized less by the human complement system, which is explained by CD46 expression on the viral membrane. The inoculation of 10 pancreatic cancer cell lines demonstrated similar or enhanced replication and cell-killing efficacy of rNDV F0-M/S compared to rNDV F0 and rNDV F0-M. In conclusion, NDV F0 variants with M and S substitutions are non-virulent, effective oncolytic viruses that can be produced in mammalian cells, potentially resulting in a more effective treatment option for pancreatic cancer patients compared to rNDV F0.

The paradigm in the field of oncolytic virotherapy proposes that tumor cell killing by an oncolytic virus (OV) culminates in the priming of antitumor CD8 T cells. However, this ignores the impact a highly immunodominant antiviral response against the OV has on the antitumor response which has been weakened by mechanisms of central tolerance. Here, we show that inflammatory Vesicular Stomatitis Virus (VSV) failed to prime an adoptively transferred, or pre-existing, population of tumor-reactive T cells. Combination with αPD1 immune checkpoint blockade therapy improved survival only when VSV expressed tumor associated antigens (TAA). These data show that, in this model, the highly inflammatory OV VSV alone actively outcompetes antitumor immunity. However, we also show that viral expression of a mutant near-self TAA can break central tolerance expanding heteroclitic self-reactive and near-self-reactive T cells, thus overcoming viral immunodominance by promoting tumor-specific T cell proliferation in parallel with expanding antiviral T cells.

Tumor microenvironment (TME) denotes the non-cancerous cells and components presented in the tumor, including molecules produced and released by them. Interactions between cancer cells, immune cells, stromal cells, and the extracellular matrix within the TME create a dynamic ecosystem that can either promote or hinder tumor growth and spread. The TME plays a pivotal role in either promoting or inhibiting tumor growth and dissemination, making it a critical factor to consider in the development of effective cancer therapies. Understanding the intricate interplay within the TME is crucial for devising effective cancer therapies. Combination therapies involving inhibitors of immune checkpoint blockade (ICB), and/or chemotherapy now offer new approaches for cancer therapy. However, it remains uncertain how to best utilize these strategies in the context of the complex tumor microenvironment. Oncogene-driven changes in tumor cell metabolism can impact the TME to limit immune responses and present barriers to cancer therapy. Cellular and acellular components in tumor microenvironment can reprogram tumor initiation, growth, invasion, metastasis, and response to therapies. Components in the TME can reprogram tumor behavior and influence responses to treatments, facilitating immune evasion, nutrient deprivation, and therapeutic resistance. Moreover, the TME can influence angiogenesis, promoting the formation of blood vessels that sustain tumor growth. Notably, the TME facilitates immune evasion, establishes a nutrient-deprived milieu, and induces therapeutic resistance, hindering treatment efficacy. A paradigm shift from a cancer-centric model to a TME-centric one has revolutionized cancer research and treatment. However, effectively targeting specific cells or pathways within the TME remains a challenge, as the complexity of the TME poses hurdles in designing precise and effective therapies. This review highlights challenges in targeting the tumor microenvironment to achieve therapeutic efficacy; explore new approaches and technologies to better decipher the tumor microenvironment; and discuss strategies to intervene in the tumor microenvironment and maximize therapeutic benefits.

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.

With the use of T cell receptor T cells (TCR-T cells) and chimeric antigen receptor T cells (CAR-T cells), T-cell immunotherapy for cancer has advanced significantly in recent years. CAR-T cell therapy has demonstrated extraordinary success when used to treat hematologic malignancies. Nevertheless, there are several barriers that prevent this achievement from being applied to solid tumors, such as challenges with tumor targeting and inadequate transit and adaption of genetically modified T-cells, especially in unfavorable tumor microenvironments The deficiencies of CAR-T cell therapy in the treatment of solid tumors are compensated for by TCR-T cells, which have a stronger homing ability to initiate intracellular commands, 90% of the proteins can be used as developmental targets, and they can recognize target antigens more broadly. As a result, TCR-T cells may be more effective in treating solid tumors. In this review, we discussed the structure of TCR-T and have outlined the drawbacks of TCR-T in cancer therapy, and suggested potential remedies. This review is crucial in understanding the current state and future potential of TCR-T cell therapy. We emphasize how important it is to use combinatorial approaches, combining new combinations of various emerging strategies with over-the-counter therapies designed for TCR-T, to increase the anti-tumor efficacy of TCR-T inside the TME and maximize treatment safety, especially when it comes to solid tumor immunotherapies.

Glioma, the deadly primary intracranial tumor, poses challenges in clinical treatment due to its infiltrative growth and resistance to radiation. Oncolytic virus therapy holds potential for the treatment of malignant gliomas, but its application is impeded by the requirement for intracranial injections due to the presence of blood-brain barrier (BBB). In this study, to overcome this limitation, the study develops a nanocapsule encapsulating the recombinant oncolytic virus EV-A71-miR124T, enabling the treatment of glioma through intravenous administration. It is demonstrated that the nanocapsule can cross the BBB and selectively release oncolytic virus at the tumor site, resulting in targeted and specific killing of glioma cells. In mice with implanted intracranial orthotopic gliomas, intravenous administration of the nanocapsule suppresses tumor growth and significantly extends survival time. Consequently, the study establishes an effective treatment method for malignant gliomas using an oncolytic virus nanocapsule through intravenous administration. These findings provide a new strategy for oncolytic virus therapy in glioma treatment and offer perspectives for targeted therapies of other brain tumors and diseases.

In recent years, cancer immunotherapy has received widespread attention due to significant tumor clearance in some malignancies. Various immunotherapy approaches, including vaccines, immune checkpoint inhibitors, oncolytic virotherapy, bispecific T cell engagers, and adoptive T cell transfer, have completed or are undergoing clinical trials for prostate cancer. Despite immune checkpoint blockade's extraordinary effectiveness in treating a variety of cancers, targeted prostate cancer treatment using the immune system is still in its infancy. Multiple factors including the heterogeneity of prostate cancer, the cold tumor microenvironment, and a low level of neoantigens, contribute to the poor immunotherapy response. Significant effort is being devoted to improving immune-based prostate cancer therapy. Recently, several key discoveries demonstrate that prostate cancer immunotherapy agents may be used to promise better prognosis for patients as part of combination strategies with other agents targeting tumor-associated immune mechanism of resistance. Here, this review comprehensively examines the recent advancements in immunotherapy for prostate cancer, exploring its potential synergistic effects when combined with other treatment modalities to enhance clinical efficacy.

Non-small cell lung cancer (NSCLC) is a major cause of cancer-related deaths globally. The study focuses on understanding the interplay between genetic mutations, cancer stem cells (CSCs), and the tumor microenvironment (TME) in driving NSCLC progression, resistance to therapies, and relapse.

A systematic search was conducted in PubMed and Scopus databases to identify significant and valuable studies relevant to NSCLC, focusing on genetic mutations, CSCs, and the TME. Articles were selected based on their relevance, methodological severity, date of publication, and scientific soundness related to NSCLC biology and therapeutic strategies. This review synthesized findings from these sources to highlight key mechanisms and potential therapeutic interventions.

Mutations in critical genes in KRAS, EGFR, TP53, and other key genes interfere with stem cell regulation, promoting CSC-like behavior, resistance to therapy, and immune evasion. The tumor microenvironment (TME), including immune cells, fibroblasts, and extracellular matrix components, further supports tumor growth and reduction in treatment efficacy. Promising strategies, including CSC targeting, TME modulation, and the development of novel biomarkers, have shown potential in preclinical and clinical studies.

The association between genetic alterations, CSCs, the TME, and other cellular pathways-including cell metabolism and immune evasion-plays a crucial role in therapy resistance, highlighting the need for comprehensive treatment strategies. The combination of genomic profiling with TME-targeting therapies could lead to personalized treatment approaches, offering hope for better clinical outcomes and reduced mortality in NSCLC patients.

Oncolytic viruses (OVs) selectively replicate within tumors, directly killing cancer cells and promoting a systemic immune response by releasing tumor antigens. These features make OVs a promising approach in tumor immunotherapy, offering targeted treatment with fewer side effects. Despite these advantages, OVs are primarily administered via intratumoral injection, limiting their effectiveness for advanced, systemic cancers. Among OVs, oncolytic adenoviruses (oAdVs) are the most widely studied due to their well-understood gene regulation, safety, and stability. In this study, a modified oAdV vector, pDC316-oAd-SA, was engineered to express the SIRPα-mIgG1Fc gene, designed to remodel tumor-associated macrophages (TAMs) and enhance anti-tumor immunity. This vector, along with a control virus (Ad-ON), was evaluated both in vitro and in vivo. The modified oAd-SA significantly improved macrophage phagocytosis and showed superior tumor regression in murine models. Additionally, while both oAdVs increased T cell infiltration in the tumor microenvironment, oAd-SA specifically enhanced T cell immune function. The study also revealed that oAdVs modulate TAMs differently across tumor types, with oAd-SA therapy particularly increasing TAM phagocytosis and promoting an anti-tumor response.

Osteosarcoma is a highly aggressive cancer in children and young adults that has a remarkably high mortality rate upon metastasis. Current standard treatments have remained largely unchanged for nearly five decades, focusing on a combination of chemotherapy with high-dose methotrexate, doxorubicin, and cisplatin, complemented by aggressive surgical resections. Despite this lack of change, recent advancements in medical research have spurred hope for more effective and less invasive approaches to managing osteosarcoma. In this review, we provide an overview of existing therapeutic modalities, including chemotherapy regimens tailored to tumor stage and patient response, radiation therapies aimed at local tumor control, and advanced surgical techniques such as limb-sparing procedures. Additionally, we explore two promising future treatments that are currently under investigation for osteosarcoma cases: targeted therapies utilizing nanomaterials like graphene oxide and innovative oncolytic viruses. This review highlights potential breakthroughs in treatment options while identifying areas that warrant further investigation in the management of osteosarcoma. Considering the limited advancements in treatment over the past decades, identifying and highlighting novel and effective therapies is vital for improving patient outcomes and survival rates.

Recently, oncolytic virus (OV) therapy has shown great promise in treating malignancies. However, intravenous safety and inherent lack of immunity are two significant limitations in clinical practice. Herein, we successfully developed a recombinant Newcastle disease virus with porcine α1,3GT gene (NDV-GT) triggering hyperacute rejection. We demonstrated its feasibility in preclinical studies. The intravenous NDV-GT showed superior ability to eradicate tumor cells in our innovative CRISPR-mediated primary hepatocellular carcinoma monkeys. Importantly, the interventional clinical trial treating 20 patients with relapsed/refractory metastatic cancer (Chinese Clinical Trial Registry of WHO, ChiCTR2000031980) showed a high rate (90.00%) of disease control and durable responses, without serious adverse events and clinically functional neutralizing antibodies, further suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of NDV-GT for immunovirotherapy. Collectively, our results demonstrate the high safety and efficacy of intravenous NDV-GT, thus providing an innovative technology for OV therapy in oncological therapeutics and beyond.