Macrophages play a central role in maintaining tissue homeostasis and in surveillance against pathogens and disease. In the lung, they can adopt either proinflammatory or anti-inflammatory states depending on the nature of the stimulus. As the predominant immune cells in both the lung tumor microenvironment and in sites of lung infection, the functional plasticity of macrophages makes them key players in determining disease outcome. Accurately defining their inflammatory profiles offers an opportunity to reprogram infection-associated macrophages towards enhanced tumor-killing phenotypes. This review explores how acute inflammation can drive macrophage-mediated antitumor immunity and highlights key molecules and signaling pathways that may be leveraged to therapeutically modulate macrophage function.

Diabetes and cancer are two of the most common public health concerns worldwide. The complex interplay of these two conditions is a growing area of research, as patients with diabetes are at increased risk for developing cancer, and vice versa. Furthermore, both patient populations show increased risk of many communicable infectious diseases and their adverse consequences, while vaccination can play a crucial role in their prevention, improving patient outcomes. Vaccination should represent a standard part of care for patients with cancer, diabetes, and both the diseases simultaneously, including people undergoing cancer treatment or in remission. Several international guidelines provide recommendations for vaccinating people with cancer or diabetes, but the two conditions have not been specifically evaluated together. Here we present a multidisciplinary consensus position paper on vaccination in patients with cancer and diabetes. The position paper is the result of a collaborative effort between experts from the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF). The paper provides a comprehensive overview of the current state-of-the-art knowledge on vaccination in patients with cancer and diabetes. It discusses the importance of vaccination in preventing infections, focuses attention on the need to consider the unique challenges faced by patients with cancer and diabetes when it comes to vaccine administration, and highlights the need for coordinated care to optimize treatment outcomes. Overall, the consensus position paper provides healthcare professionals caring for patients with cancer and diabetes recommendations on the use of various vaccines, including influenza, COVID-19, HZV, and HPV vaccines, as well as guidance on how to address common concerns and challenges related to vaccine administration.

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.

Skin cutaneous melanoma (SKCM) is a common malignant skin cancer with high mortality and recurrence rates. Although the mRNA vaccine is a promising strategy for cancer treatment, its application against SKCM remains confusing. In this study, we employed computational bioinformatics analysis to explore SKCM-associated antigens for an mRNA vaccine and suitable populations for vaccination.

Gene expression and clinical data were retrieved from GEO and TCGA. The differential expression levels and prognostic index of selected antigens were computed via GEPIA2,while genetic alterations were analyzed using cBioPortal. TIMER was utilized to assess the correlation between antigen-presenting cell infiltration and antigen. Consensus clustering identified immune subtypes, and immune characteristics were evaluated across subtypes. Weighted gene co-expression network analysis was performed to identify modules of immune-related genes.

We discovered five tumor antigens (P2RY6, PLA2G2D, RBM47, SEL1L3, and SPIB) that are significantly increased and mutated, which correlate with the survival of patients and the presence of immune cells that present these antigens. Our analysis revealed two distinct immune subtypes among the SKCM samples. Immune subtype 1 was associated with poorer clinical outcomes and exhibited low levels of immune activity, characterized by fewer mutations and lower immune cell infiltration. In contrast, immune subtype 2 showed higher immune activity and better patient outcomes. Subsequently, the immune landscape of SKCM exhibited immune heterogeneity among patients, and a key gene module that is enriched in immune-related pathways was identified.

Our findings suggest that the identified tumor antigens could serve as valuable targets for developing mRNA vaccines against SKCM, particularly for patients in immune subtype 1. This research provides valuable insights into personalized immunotherapy approaches for this challenging cancer and highlights the advantages of bioinformatics in identifying immune targets and optimizing treatment approaches.

Immunotherapies are effective for cancer treatment but are limited in 'cold' tumor microenvironments due to a lack of infiltrating CD8+ T cells, key players in the anti-cancer immune response. The onset of the COVID-19 pandemic sparked the widespread use of mRNA-formulated vaccines and is well documented that vaccination induces a Th1-skewed immune response. Here, we evaluated the effects of an intratumoral injection of the mRNA COVID-19 vaccine in subcutaneous melanoma tumor mouse models. Tumor growth and survival studies following a single intratumoral injection of the COVID-19 vaccine showed significant tumor suppression and prolonged survival in established B16F10 subcutaneous tumor-bearing mice. mRNA vaccine treatment resulted in a significant increase in CD8+ T cell infiltration into the tumor microenvironment, as observed using intravital imaging and flow cytometry. Further tumor growth suppression was achieved using additional mRNA vaccine treatments. Combination administration of mRNA vaccine with immune checkpoint therapies demonstrated enhanced effects, further delaying tumor growth and improving the survival time of tumor-bearing mice. This study demonstrates that mRNA vaccines may be used as adjuvants for immunotherapies.

Many patients with breast cancer use complementary and alternative medicine (CAM) including mistletoe preparations (Viscum album extracts, VAE). CAM alone has been associated with poor outcomes. Few, if any, confirmed breast cancer remissions have been reported with CAM treatment alone.

Case 1: 60-year-old female with a histologically confirmed local recurrence of hormone receptor positive (HR+) Her2/neu negative (HER2-) breast cancer 3 years after the initial diagnosis and treatment. The patient declined conventional therapies and was treated with intratumoral VAE plus intratumoral influenza vaccine (IV) and concurrent VAE-induced hyperthermia. Lumpectomy 5 months later confirmed a near pathological complete remission (near pCR). Follow-up at 3 years confirms durable remission. Case 2: 57-year-old female with histologically confirmed HR+, HER2- right sided breast cancer with 2-[18F]FDG-PET/computed tomography (CT) positive metastatic disease who declined conventional treatment. The patient was treated with 17 monthly cycles of VAE-induced hyperthermia, eight of which included intratumoral VAE, four of these eight including intratumoral IV. Almost 2 years after treatment start, a follow-up 2-[18F]FDG-PET/CT showed marked morphological and metabolic reduction of breast tumor on the right side, stable local lymph node metastases in the right axilla, complete remission of pulmonary metastases, the single bone metastasis, and the majority of hilomediastinal lymph node metastases but a new metabolic highly active left adrenal lesion.

Clinical studies of intratumoral VAE-influenza vaccine with concurrent VAE-induced hyperthermia in ER positive HER2/neu negative breast cancer are warranted.

Non-small cell lung cancer (NSCLC), the most prevalent form of lung cancer, remains a leading cause of cancer-related mortality worldwide, particularly among elderly individuals. The phenomenon of immunosenescence, characterized by the progressive decline in immune cell functionality with aging, plays a pivotal role in NSCLC progression and contributes to the diminished efficacy of therapeutic interventions in older patients. Immunosenescence manifests through impaired immune surveillance, reduced cytotoxic responses, and increased chronic inflammation, collectively fostering a pro-tumorigenic microenvironment. This review provides a comprehensive analysis of the molecular, cellular, and genetic mechanisms of immunosenescence and its impact on immune surveillance and the tumor microenvironment (TME) in NSCLC. We explore how aging affects various immune cells, including T cells, B cells, NK cells, and macrophages, and how these changes compromise the immune system's ability to detect and eliminate tumor cells. Furthermore, we address the challenges posed by immunosenescence to current therapeutic strategies, particularly immunotherapy, which faces significant hurdles in elderly patients due to immune dysfunction. The review highlights emerging technologies, such as single-cell sequencing and CRISPR-Cas9, which offer new insights into immunosenescence and its potential as a therapeutic target. Finally, we outline future research directions, including strategies for rejuvenating the aging immune system and optimizing immunotherapy for older NSCLC patients, with the goal of improving treatment efficacy and survival outcomes. These efforts hold promise for the development of more effective, personalized therapies for elderly patients with NSCLC.

Immunogenic cell death (ICD) of tumor cells, which is characterized by releasing immunostimulatory "find me" and "eat me" signals, expressing proinflammatory cytokines and providing personalized and broad-spectrum tumor antigens draws increasing attention in developing a tumor vaccine. In this study, we aimed to investigate whether the influenza virus (IAV) is efficient enough to induce ICD in tumor cells and an extra modification of IAV components such as hemeagglutinin (HA) will be helpful for the ICD-induced cells to elicit robust antitumor effects; in addition, to evaluate whether the membrane-engineering polylactic coglycolic acid nanoparticles (PLGA NPs) simulating ICD immune stimulation mechanisms hold the potential to be a promising vaccine candidate, a mouse melanoma cell line (B16-F10 cell) was infected with IAV rescued by the reverse genetic system, and the prepared cells and membrane-modified PLGA NPs were used separately to immunize the melanoma-bearing mice. IAV-infected tumor cells exhibit dying status, releasing high mobility group box-1 (HMGB1) and adenosine triphosphate (ATP), and exposing calreticulin (CRT), IAV hemeagglutinin (HA), and tumor antigens like tyrosinase-related protein 2 (TRP2). IAV-induced ICD cells enhance biomass-derived carbon (BMDCs) migration, antigen uptake, cross-presentation, and maturation in vitro. Furthermore, immunization with IAV-induced ICD cells effectively suppressed tumor growth in melanoma-bearing mice. The isolated cell membrane inherited the immunological characteristics from the ICD cells and elicited robust antitumor immune responses through decorating PLGA NPs loading with a tumor-specific helper T-cell peptide and supplemented with ATP in a hydrogel system. This study indicated a promising strategy for developing cell-based and personalized tumor vaccines through fully taking advantage of the immune stimulation mechanisms of ICD occurrence in tumor cells, IAV modification, and nanoscale delivery.

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.

Immuno-oncology has witnessed remarkable advancements in the past decade, revolutionizing the landscape of cancer therapeutics in an encouraging manner. Among the diverse immunotherapy strategies, mRNA vaccines have ushered in a new era for the therapeutic management of malignant diseases, primarily due to their impressive impact on the COVID-19 pandemic. In this comprehensive review, we offer a systematic overview of mRNA vaccines, focusing on the optimization of structural design, the crucial role of delivery materials, and the administration route. Additionally, we summarize preclinical studies and clinical trials to provide valuable insights into the current status of mRNA vaccines in cancer treatment. Furthermore, we delve into a systematic discussion on the significant challenges facing the current development of mRNA tumor vaccines. These challenges encompass both intrinsic and external factors that are closely intertwined with the successful application of this innovative approach. To pave the way for a more promising future in cancer treatments, a deeper understanding of immunological mechanisms, an increasing number of high-quality clinical trials, and a well-established manufacturing platform are crucial. Collaborative efforts between scientists, clinicians, and industry engineers are essential to achieving these goals.

We investigated a novel cancer immunotherapy strategy that effectively suppresses tumor growth in multiple solid tumor models and significantly extends the lifespan of tumor-bearing mice by introducing pathogen antigens into tumors via mRNA-lipid nanoparticles. The pre-existing immunity against the pathogen antigen can significantly enhance the efficacy of this approach. In mice previously immunized with BNT162b2, an mRNA-based COVID-19 vaccine encoding the spike protein of the SARS-CoV-2 virus, intratumoral injections of the same vaccine efficiently tagged the tumor cells with mRNA-expressed spike protein. This action rapidly mobilized the pre-existing memory immunity against SARS-CoV-2 to kill the cancer cells displaying the spike protein, while concurrently reprogramming the tumor microenvironment (TME) by attracting immune cells. The partial elimination of tumor cells in a normalized TME further triggered extensive tumor antigen-specific T cell responses through antigen spreading, eventually resulting in potent and systemic tumor-targeting immune responses. Moreover, combining BNT162b2 treatment with anti-PD-L1 therapy yielded a more substantial therapeutic impact, even in "cold tumor" types that are typically less responsive to treatment. Given that the majority of the global population has acquired memory immunity against various pathogens through infection or vaccination, we believe that, in addition to utilizing the widely held immune memory against SARS-CoV-2 via COVID-19 vaccine, mRNA vaccines against other pathogens, such as Hepatitis B Virus (HBV), Common Human Coronaviruses (HCoVs), and the influenza virus, could be rapidly transitioned into clinical use and holds great promise in treating different types of cancer. The extensive selection of pathogen antigens expands therapeutic opportunities and may also overcome potential drug resistance.

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor characterized by poor prognosis and lack of effective treatments. In recent years, peptide vaccines that use sequences based on tumor-specific or tumor-associated antigens to activate immune responses against tumor cells have emerged as a new therapeutic strategy. In this study, we developed a novel therapeutic polypeptide vaccine targeting the tumor-associated antigen Fibrinogen-Like Protein 2 (FGL2), whose dominant epitope peptide was tandemly linked to the C-terminus of HCMV-IE1mut via a linker. We used this vaccine to compare the therapeutic efficacy of HCMV-IE1mut alone versus HCMV-IE1mut-FGL2172-220 and investigate the potential mechanism of action of HCMV-IE1mut-FGL2172-220 in glioma treatment. An in situ GBM model (GL261-IE1-luc cells) was used to determine the efficacy of the vaccine. Treatment with HCMV-IE1mut-FGL2172-220 exerted antitumor effects and extended the survival of the GL261 animal model. We observed reduced proportions of microglia, regulatory T cells (Treg), and myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME) by immunofluorescence. Flow cytometry showed that compared to HCMV-IE1mut alone, treatment with HCMV-IE1mut-FGL2172-220 increased the proportion of CD8+ T cells and tissue-resident memory T cells (TRM). ELISA analysis showed that it improved the secretion of tumor-specific IFN-γ and TNF-α by these cells and downregulated the expression of IL-6 and IL-10. Our study demonstrates that the long-peptide FGL2172-220 improves the antitumor efficacy of HCMV-IE1mut, possibly by reshaping immune cells in the glioma microenvironment. These findings lay the groundwork for the development of therapeutic antigenic peptide vaccines to improve antitumor effects for cancer.

The immune system is endowed with the capacity to distinguish between self and non-self, so-called immune tolerance or "consciousness of the immune system." This type of awareness is designed to achieve host protection by eliminating cells expressing a wide range of non-self antigens including microbial-derived peptides. Such a successful immune response is associated with the secretion of a whole spectrum of soluble mediators, e.g., cytokines and chemokines, which not only contribute to the clearance of infected host cells but also activate T cells that are not specific to the original cognate antigen. This kind of non-specific T-cell activation is called "bystander activation." Although it is well-established that this phenomenon is cytokine-dependent, there is evidence in the literature showing the involvement of peptide/MHC recognition depending on the type of T-cell subset (naive vs. memory). Here, we will summarize our current understanding of the mechanism(s) of bystander T-cell activation as well as its biological significance in a wide range of diseases including microbial infections, cancer, auto- and alloimmunity, and chronic inflammatory diseases such as atherosclerosis.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. The pathogenesis of CRC is a testament to the dysregulation of these signaling cascades, which culminates in the malignant transformation of colonic epithelium. This review aims to dissect the foundational signaling mechanisms implicated in CRC, to elucidate the generalized principles underpinning neoplastic evolution and progression. We discuss the molecular hallmarks of CRC, including the genomic, epigenomic and microbial features of CRC to highlight the role of signal transduction in the orchestration of the tumorigenic process. Concurrently, we review the advent of targeted and immune therapies in CRC, assessing their impact on the current clinical landscape. The development of these therapies has been informed by a deepening understanding of oncogenic signaling, leading to the identification of key nodes within these networks that can be exploited pharmacologically. Furthermore, we explore the potential of integrating AI to enhance the precision of therapeutic targeting and patient stratification, emphasizing their role in personalized medicine. In summary, our review captures the dynamic interplay between aberrant signaling in CRC pathogenesis and the concerted efforts to counteract these changes through targeted therapeutic strategies, ultimately aiming to pave the way for improved prognosis and personalized treatment modalities in colorectal cancer.

Respiratory tract infections represent a significant global public health concern, disproportionately affecting vulnerable populations such as children, the elderly, and immunocompromised individuals. RNA viruses, particularly influenza viruses and coronaviruses, significantly contribute to respiratory illnesses, especially in immunosuppressed and elderly individuals. Influenza A viruses (IAVs) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to pose global health threats due to their capacity to cause annual epidemics, with profound implications for public health. In addition, the increase in global life expectancy is influencing the dynamics and outcomes of respiratory viral infections. Understanding the molecular mechanisms by which IAVs and SARS-CoV-2 contribute to lung disease progression is therefore crucial. The aim of this review is to comprehensively explore the impact of IAVs and SARS-CoV-2 on chronic lung diseases, with a specific focus on pulmonary fibrosis in the elderly. It also outlines potential preventive and therapeutic strategies and suggests directions for future research.

Therapeutic cancer vaccines are among the first FDA-approved cancer immunotherapies. Among them, it remains a major challenge to achieve robust lymph-node (LN) accumulation. However, delivering cargo into LN is difficult owing to the unique structure of the lymphatics, and clinical responses have been largely disappointing. Herein, inspired by the Migrated-DCs homing from the periphery to the LNs, an injectable hydrogel-based polypeptide vaccine system is described for enhancing immunostimulatory efficacy, which could form a local niche of vaccine "hitchhiking" on DCs. The OVA peptide modified by lipophilic DSPE domains in the hydrogel is spontaneously inserted into the cell membrane to achieve "antigen anchoring" on DCs in vivo. Overall, OVA peptide achieves active access LNs through recruiting and "hitchhiking" subcutaneous Migrated-DCs. Remarkably, it is demonstrated that the composite hydrogel enhances LNs targeting efficacy by approximately six-fold compared to free OVA peptide. Then, OVA peptide can be removed from the cell surface under a typical acidic microenvironment within the LNs, further share them with LN-resident APCs via the "One-to-Many" strategy (One Migrated-DC corresponding to Many LN-resident APCs), thereby activating powerful immune stimulation. Moreover, the hydrogel vaccine exhibits significant tumor growth inhibition in melanoma and inhibits pulmonary metastatic nodule formation.

The landscape of current tumor treatment has been revolutionized by the advent of immunotherapy based on PD-1/PD-L1 inhibitors. Leveraging its capacity to mobilize systemic antitumor immunity, which is primarily mediated by T cells, there is growing exploration and expansion of its potential value in various stages of clinical tumor treatment. Neoadjuvant immunotherapy induces a robust immune response against tumors prior to surgery, effectively facilitating tumor volume reduction, early eradication or suppression of tumor cell activity, and control of potential metastatic spread, to improve curative surgical resection rates, and prevent tumor recurrence. This review delineates the theoretical basis of neoadjuvant immunotherapy from preclinical research evidence, discusses specific challenges in clinical application, and provides a comprehensive overview of clinical research progress in neoadjuvant immunotherapy for gastrointestinal tumors. These findings suggest that neoadjuvant immunotherapy has the potential to ameliorate immunosuppressive states and enhance cytotoxic T cell function while preserving lymphatic drainage in the preoperative period. However, further investigations are needed on specific treatment regimens, suitable patient populations, and measurable endpoints. Despite numerous studies demonstrating the promising efficacy and manageable adverse events of neoadjuvant immunotherapy in gastrointestinal tumors, the availability of high-quality randomized controlled trials is limited, which highlights the necessity for further research.

Triple negative breast cancer (TNBC) exhibits limited responsiveness to immunotherapy owing to its immunosuppressive tumor microenvironment (TME). Here, a reactive oxygen species (ROS)-labile nanodrug encapsulating the photosensitizer Ce6 and Bcl-2 inhibitor ABT-737 was developed to provoke a robust immune response via the synergistic effect of photodynamic therapy (PDT) and the reversal of apoptosis resistance. Upon exposure to first-wave near-infrared laser irradiation, the generated ROS triggers PEG cleavage, facilitating the accumulation of the nanodrug at tumor region and endocytosis by tumor cells. Further irradiation leads to the substantial generation of cytotoxic ROS, initiating an immunogenic cell death (ICD) cascade, which prompts the maturation of dendritic cells (DCs) as well as the infiltration of T cells into the tumor site. Meanwhile, Bcl-2 inhibition counteracts apoptosis resistance, thereby amplifying PDT-induced ICD and bolstering antitumor immunity. As a result, the ROS-sensitive nanodrug demonstrates a potent inhibitory effect on tumor growth.

Oncolytic viral therapy (OVT) is a novel anti-tumor immunotherapy approach, specifically replicating within tumor cells. Currently, oncolytic viruses are mainly administered by intratumoral injection. However, achieving good results for distant metastatic tumors is challenging. In this study, a multifunctional oncolytic adenovirus, OA@CuMnCs, was developed using bimetallic ions copper and manganese. These metal cations form a biomineralized coating on the virus's surface, reducing immune clearance. It is known that viruses upregulate the expression of PD-L1. Copper ions in OA@CuMnCs can decrease the PD-L1 expression of tumor cells, thereby promoting immune cell-related factor release. This process involves antigen presentation and the combination of immature dendritic cells, transforming them into mature dendritic cells. It changes "cold" tumors into "hot" tumors, further inducing immunogenic cell death. While oncolytic virus replication requires oxygen, manganese ions in OA@CuMnCs can react with endogenous hydrogen peroxide. This reaction produces oxygen, enhancing the virus's replication ability and the tumor lysis effect. Thus, this multifunctionally coated OA@CuMnCs demonstrates potent amplification in immunotherapy efficacy, and shows great potential for further clinical OVT. STATEMENT OF SIGNIFICANCE: Oncolytic virus therapy (OVs) is a new anti-tumor immunotherapy method that can specifically replicate in tumor cells. Although the oncolytic virus can achieve a therapeutic effect on some non-metastatic tumors through direct intratumoral injection, there are still three major defects in the treatment of metastatic tumors: immune response, hypoxia effect, and administration route. Various studies have shown that the immune response in vivo can be overcome by modifying or wrapping the surface protein of the oncolytic virus. In this paper, a multifunctional coating of copper and manganese was prepared by combining the advantages of copper and manganese ions. The coating has a simple preparation method and mild conditions, and can effectively enhance tumor immunotherapy.

Tumor metastasis significantly impacts the prognosis of non-small cell lung cancer (NSCLC) patients, with lymph node (LN) metastasis being the most common and early form of spread. With the development of adjuvant immunotherapy, increasing attention has been paid to the tumor-draining lymph nodes（TDLN) in early-stage NSCLC, especially tumor-metastatic lymph nodes, which provides poor prognostic information but has potential benefits in adjuvant treatment.

We showed the remodeled immune environment in TDLNs through using TCR-seq to analyse 24 primary lung cancer tissues and 134 LNs from 24 lung cancer patients with or without LN metastasis. Additionally, we characterized the spatial profiling of immunocytes and tumor cells in TDLNs and primary tumor sites through using multi-IHC.

We found the remodeled immune environment in TDLNs through analyzing primary lung cancer tissues and LNs from NSCLC patients with or without LN metastasis. Considering the intricate communication between tumor and immunocytes, we further subdivided TDLNs, revealing that metastasis-negative LNs from LN-metastatic patients (MNLN) exhibited greater immune activation, exhaustion, and memory in comparison to both metastasis-positive LNs (MPLN) and TDLNs from non-LN-metastatic patients (NMLN).

Our data indicate that LN metastasis facilitated tumor-specific antigen presentation in TDLNs and induces T cell priming, while existing tumor cells generate an immune-suppressive environment in MPLNs through multiple mechanisms. These findings contribute to a comprehensive understanding of the immunological mechanisms through which LN metastasis influences tumor progression and plays a role in immunotherapy for NSCLC patients.

Tumors remain one of the major threats to public health and there is an urgent need to design new pharmaceutical agents for their diagnosis and treatment. In recent years, due to the rapid development of nanotechnology, biotechnology, catalytic science, and theoretical computing, subtlety has gradually made great progress in research related to tumor diagnosis and treatment. Compared to conventional drugs, enzymes can improve drug distribution and enhance drug enrichment at the tumor site, thereby reducing drug side effects and enhancing drug efficacy. Nanozymes can also be used as tumor tracking imaging agents to reshape the tumor microenvironment, providing a versatile platform for the diagnosis and treatment of malignancies. In this paper, we review the current status of research on enzymes in oncology and analyze novel oncology therapeutic approaches and related mechanisms. To date, a large number of nanomaterials, such as noble metal nanomaterials, nonmetallic nanomaterials, and carbon-based nanomaterials, have been shown to be able to function like natural enzymes, particularly with significant advantages in tumor therapy. In light of this, the authors in this review have systematically summarized and evaluated the construction, enzymatic activity, and their characteristics of nanozymes with respect to current modalities of tumor treatment. In addition, the application and research progress of different types of nicknames and their features in recent years are summarized in detail. We conclude with a summary and outlook on the study of nanozymes in tumor diagnosis and treatment. It is hoped that this review will inspire researchers in the fields of nanotechnology, chemistry, biology, materials science and theoretical computing, and contribute to the development of nano-enzymology.

Immune checkpoint therapies (ICT) have transformed the treatment of cancer over the past decade. However, many patients do not respond or suffer relapses. Successful immunotherapy requires epitope spreading, but the slow or inefficient induction of functional antitumoral immunity delays the benefit to patients or causes resistances. Therefore, understanding the key mechanisms that support epitope spreading is essential to improve immunotherapy. In this review, we highlight the major role played by B-cells in breaking immune tolerance by epitope spreading. Activated B-cells are key Antigen-Presenting Cells (APC) that diversify the T-cell response against self-antigens, such as ribonucleoproteins, in autoimmunity but also during successful cancer immunotherapy. This has important implications for the design of future cancer vaccines.

Colorectal cancer (CRC) is the third most common cancer globally and presents a significant challenge owing to its high mortality rate and the limitations of traditional treatment options such as surgery, radiotherapy, and chemotherapy. While these treatments are foundational, they are often poorly effective owing to tumor resistance. Immunotherapy is a groundbreaking alternative that has recently emerged and offers new hope for success by exploiting the body's own immune system. This article aims to provide an extensive review of clinical trials evaluating the efficacy of various immunotherapies, including CRC vaccines, chimeric antigen receptor T-cell therapies, and immune checkpoint inhibitors. We also discuss combining CRC vaccines with monoclonal antibodies, delve into preclinical studies of novel cancer vaccines, and assess the impact of these treatment methods on patient outcomes. This review seeks to provide a deeper understanding of the current state of CRC treatment by evaluating innovative treatments and their potential to redefine the prognosis of patients with CRC.

The development of cancer neoantigen vaccines that prime the anti-tumor immune responses has been hindered in part by challenges in delivery of neoantigens to the tumor. Here, using the model antigen ovalbumin (OVA) in a melanoma model, we demonstrate a chimeric antigenic peptide influenza virus (CAP-Flu) system for delivery of antigenic peptides bound to influenza A virus (IAV) to the lung. We conjugated attenuated IAVs with the innate immunostimulatory agent CpG and, after intranasal administration to the mouse lung, observed increased immune cell infiltration to the tumor. OVA was then covalently displayed on IAV-CPG using click chemistry. Vaccination with this construct yielded robust antigen uptake by dendritic cells, a specific immune cell response and a significant increase in tumor-infiltrating lymphocytes compared to peptides alone. Lastly, we engineered the IAV to express anti-PD1-L1 nanobodies that further enhanced regression of lung metastases and prolonged mouse survival after rechallenge. Engineered IAVs can be equipped with any tumor neoantigen of interest to generate lung cancer vaccines.

Toll-like receptors (TLRs) are well-known for their role in cancer development as well as in directing anti-tumor immunity. Because TLRs have also been implicated in the innate recognition of the influenza virus, it was of great interest to investigate the potential TLRs' contribution to the reduction in tumor growth following intratumoral injection of an unadjuvanted influenza vaccine and the lack of antitumor response from an adjuvanted vaccine. In our previous publication, we showed that the unadjuvanted flu vaccine modulates TLR7 expression leading to anti-tumor response in a murine model of melanoma. Here, we show that the unadjuvanted and adjuvanted flu vaccines robustly stimulate different sets of TLRs, TLR3 and TLR7, and TLR4 and TLR9, respectively. In addition, the reduction in tumor growth and improved survival from intratumoral administration of the unadjuvanted vaccine was found to be diminished in TLR7-deficient mice. Finally, we observed that both vaccines have the capacity to modulate TLR expression on both innate and adaptive immune cells. Our findings add to the mechanistic understanding of the parameters that influence tumor outcomes in unadjuvanted and adjuvanted influenza vaccines.

Oncolytic viruses (OVs), viruses engineered to lyse tumor cells, work hand in hand with the immune response. While for decades the field isolated lytic capability and viral spread to increase response to virotherapy, there is now a wealth of research that demonstrates the importance of immunity in the OV mechanism of action. In this review, we will cover how OVs interact with the innate immune system to fully activate the adaptive immune system and yield exceptional tumor clearances as well as look forward at combination therapies which can improve clinical responses.

As one of the malignant tumors with high incidence rate and high mortality, lung cancer seriously threatens the life safety of patients. Research shows that microorganisms are closely related to lung cancer. The microbiome is symbiotic with the host and plays a vital role in the functions of the human body. Microbiota dysbiosis is correlated with development of lung cancer. However, the underlying mechanisms are poorly understood. This paper summarizes the composition characteristics of the gut-lung axis microbiome and intratumoral microbiome in patients with lung cancer. We then expound five potential carcinogenic mechanisms based on microorganisms, such as genotoxicity, metabolism, inflammation, immune response, and angiogenesis. Next, we list three high-throughput sequencing methods, and finally looks forward to the prospect of microorganisms as novel targets for early diagnosis and treatment of lung cancer.

Mucosal tissues are frequent targets of both primary and metastatic cancers. This has highlighted the significance of both innate and adaptive anti-cancer immunity at mucosal sites. Trained innate immunity (TII) is an emerging concept defined as enhanced reactivity of innate leukocytes long after a previous stimulation that induces prolonged epigenetic, transcriptional, and metabolic changes. Trained innate leukocytes can respond to heterologous targets due to their lacking of antigen-specificity in most cases. Emerging experimental and clinical data suggest that certain microbes or their products induce TII in mucosal-associated innate leukocytes which endows heterologous anti-tumor innate immunity, in both prophylactic and therapeutic scenarios. In this mini-review, we summarize updated findings on the significance of TII in mucosal cancers. We also attempt to raise a few key questions critical to our further understanding on the roles of TII in mucosal cancers, and to the potential application of TII as anti-cancer strategy.

To improve the efficacy of immune checkpoint inhibitors (ICIs) for cancer treatment, various strategies, including combination therapies with repurposed drugs, are being explored. Several readily available interventions with potential to enhance programmed death 1 (PD-1) blockade have been identified. However, these interventions often remain overlooked due to the lack of financial incentives for their development, making them financial orphans. This review summarizes current knowledge regarding off-label drugs, supplements, and other readily available interventions that could improve the efficacy of PD-1 blockade. The summary of each intervention includes the proposed mechanism of action for combination with checkpoint inhibitors and data from animal and human studies. Additionally, we include summaries of common interventions to be avoided by patients on PD-1 blockade. Finally, we present approaches for conducting further studies in patients, with the aim of expediting the clinical development of these interventions. We strive to increase awareness of readily available combination therapies that may advance cancer immunotherapy and help patients today.

Breast cancer continues to have a high disease burden worldwide and presents an urgent need for novel therapeutic strategies to improve outcomes. The influenza vaccine offers a unique approach to enhance the anti-tumor immune response in patients with breast cancer. Our study explores the intratumoral use of the influenza vaccine in a triple-negative 4T1 mouse model of breast cancer. We show that the influenza vaccine attenuated tumor growth using a three-dose intratumoral regimen. More importantly, prior vaccination did not alter this improved anti-tumor response. Furthermore, we characterized the effect that the influenza vaccine has on the tumor microenvironment and the underlying mechanisms of action. We established that the vaccine facilitated favorable shifts in restructuring the tumor microenvironment. Additionally, we show that the vaccine's ability to bind sialic acid residues, which have been implicated in having oncogenic functions, emerged as a key mechanism of action. Influenza hemagglutinin demonstrated binding ability to breast cancer cells through sialic acid expression. When administered intratumorally, the influenza vaccine offers a promising therapeutic strategy for breast cancer patients by reshaping the tumor microenvironment and modestly suppressing tumor growth. Its interaction with sialic acids has implications for effective therapeutic application and future research.

Low pathogenic influenza A viruses (IAVs) have shown promising oncolytic potential in lung cancer-bearing mice. However, as replication-competent pathogens, they may cause side effects in immunocompromised cancer patients. To circumvent this problem, we genetically engineered nonreplicating IAVs lacking the hemagglutinin (HA) gene (ΔHA IAVs), but reconstituted the viral envelope with recombinant HA proteins to allow a single infection cycle. To optimize the therapeutic potential and improve immunomodulatory properties, these replication-incompetent IAVs were complemented with a murine interferon-gamma (mIFN-γ) gene. After intratracheal administration to transgenic mice that develop non-small cell lung cancer (NSCLC), the ΔHA IAVs induced potent tumor destruction. However, ΔHA IAVs armed with mIFN-γ exhibited an even stronger and more sustained effect, achieving 85% tumor reduction at day 12 postinfection. In addition, ΔHA-mIFN-γ viruses were proven to be efficient in recruiting and activating natural killer cells and macrophages from the periphery and in inducing cytotoxic T lymphocytes. Most important, both viruses, and particularly IFN-γ-encoding viruses, activated tumor-associated alveolar macrophages toward a proinflammatory M1-like phenotype. Therefore, replication-incompetent ΔHA-mIFN-γ-IAVs are safe and efficient oncolytic viruses that additionally exhibit immune cell activating properties and thus represent a promising innovative therapeutic option in the fight against NSCLC.

Two new series of complexes with pyridine-containing Schiff bases, [VV O(SALIEP)L] and [VV O(Cl-SALIEP)L] (SALIEP=N-(salicylideneaminato)-2-(2-aminoethylpyridine; Cl-SALIEP=N-(5-chlorosalicylideneaminato)-2-(2-aminoethyl)pyridine, L=catecholato(2-) ligand) have been synthesized. Characterization by 1 H and 51 V NMR and UV-Vis spectroscopies confirmed that: 1) most complexes form two major geometric isomers in solution, and [VV O(SALIEP)(DTB)] (DTB=3,5-di-tert-butylcatecholato(2-)) forms two isomers that equilibrate in solution; and 2) tert-butyl substituents were necessary to stabilize the reduced VIV species (EPR spectroscopy and cyclic voltammetry). The pyridine moiety within the Schiff base ligands significantly changed their chemical properties with unsubstituted catecholate ligands compared with the parent HSHED (N-(salicylideneaminato)-N'-(2-hydroxyethyl)-1,2-ethanediamine) Schiff base complexes. Immediate reduction to VIV occurred for the unsubstituted-catecholato VV complexes on dissolution in DMSO. By contrast, the pyridine moiety within the Schiff base significantly improved the hydrolytic stability of [VV O(SALIEP)(DTB)] compared with [VV O(HSHED)(DTB)]. [VV O(SALIEP)(DTB)] had moderate stability in cell culture media. There was significant cellular uptake of the intact complex by T98G (human glioblastoma) cells and very good anti-proliferative activity (IC50 6.7±0.9 μM, 72 h), which was approximately five times higher than for the non-cancerous human cell line, HFF-1 (IC50 34±10 μM). This made [VV O(SALIEP)(DTB)] a potential drug candidate for the treatment of advanced gliomas by intracranial injection.

Hypoxia, which can considerably affect the tumor microenvironment, hinders the use of immunotherapy in bladder cancer (BLCA). Therefore, we aimed to identify reliable hypoxia-related biomarkers to guide clinical immunotherapy in BLCA.

Using data downloaded from TCGA-BLCA cohort, we determined BLCA subtypes which divide 408 samples into different subtypes. Tumor immune infiltration levels of two clusters were quantified using ssGSEA, MCPcounter, EPIC, ESTIMATE, and TIMER algorithms. Next, we constructed a hypoxia score based on the expression of hypoxia-related genes. The IMvigor210 cohort and SubMap analysis were used to predict immunotherapeutic responses in patients with different hypoxia scores. Hub genes were screened using cytoscape, immunohistochemistry (IHC), and multispectral immunofluorescence were used to detect the spatial distribution of immune markers.

Patients with BLCA were categorized into cluster1 (n = 227) and Cluster2 (n = 181). Immune infiltration and expression of immune markers were higher in Cluster1. Immune infiltration was also more obvious in the high-hypoxia score group which related to a better predicted response to immunotherapy. IHC, and multispectral immunofluorescence confirmed the importance of TLR8 in immune infiltration and immune phenotype.

BLCA subtype can evaluate the infiltration of immune cells in the tumor microenvironment of different patients. Hypoxia score in this study could effectively predict immunotherapeutic responses in patients with BLCA. TLR8 may be a potential target for clinical immunotherapy.

The clinical management of advanced malignancies of the upper and lower urinary tract has been revolutionized with the advent of immune checkpoint blockers (ICBs). ICBs reinstate or bolster pre-existing immune responses while creating new T cell specificities. Immunogenic cancers, which tend to benefit more from immunotherapy than cold tumours, harbour tumour-specific neoantigens, often associated with a high tumour mutational burden, as well as CD8+ T cell infiltrates and ectopic lymphoid structures. The identification of beneficial non-self tumour antigens and natural adjuvants is the focus of current investigation. Moreover, growing evidence suggests that urinary or intestinal commensals, BCG and uropathogenic Escherichia coli influence long-term responses in patients with kidney or bladder cancer treated with ICBs. Bacteria infecting urothelium could be a prominent target for T follicular helper cells and B cells, linking innate and cognate CD8+ memory responses. In the urinary tract, commensal flora differ between healthy and tumoural mucosae. Although antibiotics can affect the prognosis of urinary tract malignancies, bacteria can have a major influence on cancer immunosurveillance. Beyond their role as biomarkers, immune responses against uropathogenic commensals could be harnessed for the design of future immunoadjuvants that can be advantageously combined with ICBs.

Chronic kidney disease (CKD) patients possess a higher risk for renal cell carcinoma (RCC) possibly because of related underlying inflammation and immune dysregulation. In the current population-based cohort study, we evaluate the effects of influenza vaccination on RCC among CKD patients.

We analysed the vaccinated and unvaccinated CKD patients (≥55 years of age) identified from the Taiwan National Health Insurance Database. Propensity score matching was used to reduce the selection bias. Subgroup analyses based on comorbid conditions, dialysis status and vaccinated dosages were also conducted.

The incidence of RCC decreased significantly in the vaccinated compared with unvaccinated group {unadjusted hazard ratio [HR] 0.50 [95% confidence interval (CI) 0.31-0.81], P < .01; adjusted HR 0.46 [95% CI 0.28-0.75], P < .01}. Such protective effects of influenza vaccination were noted significantly among those ≥75 years of age [unadjusted HR 0.29 (95% CI 0.12-0.74), P < .01; adjusted HR 0.22 (95% CI 0.08-0.58), P < .01]. A reverse association was noted between the total number of vaccinations and RCC events in both unadjusted and adjusted models. The Kaplan-Meier estimates of the RCC events showed significantly higher free survival rates in the vaccinated as compared with the unvaccinated patients (logrank P = .005).

This population-based cohort study found a significant inverse relationship between influenza vaccination and the risk of RCC in CKD patients and the protective effects were more prominent in patients >75 years of age. A possible relation exists between the total number of vaccinations and RCC events. Future randomized clinical and basic studies will be needed to prove these findings and underlying pathophysiological mechanisms.

Objectives: Lung cancer is a main contributor to all newly diagnosed cancers worldwide. The chemoprotective effect of the influenza vaccine among patients with hypertension remains unclear. Methods: A total of 37,022 patients with hypertension were retrospectively enrolled from the Taiwan National Health Insurance Research Database. These patients were further divided into a vaccinated group (n = 15,697) and an unvaccinated group (n = 21,325). Results: After adjusting for sex, age, comorbidities, medications, level of urbanization and monthly income, vaccinated patients had a significantly lower risk of lung cancer occurrence than unvaccinated patients (adjusted hazard ratio [aHR]: 0.56, 95% confidence interval [CI]: 0.47-0.67). A potential protective effect was observed for both sexes and in the elderly age group. With a greater total number of vaccinations, a potentially greater protective effect was observed (aHR: 0.75, 95% CI 0.60-0.95; aHR: 0.66, 95% CI: 0.53-0.82; aHR: 0.26, 95% CI: 0.19-0.36, after receiving 1, 2-3 and ≥4 vaccinations, respectively). Conclusion: Influenza vaccination was associated with a lower risk of lung cancer among patients with hypertension. The potentially chemoprotective effect appeared to be dose dependent.