The next frontier in immunotherapy: potential and challenges of CAR-macrophages.

Chimeric antigen receptor macrophage (CAR-MΦ) represents a significant advancement in immunotherapy, especially for treating solid tumors where traditional CAR-T therapies face limitations. CAR-MΦ offers a promising approach to target and eradicate tumor cells by utilizing macrophages' phagocytic and antigen-presenting abilities. However, challenges such as the complex tumor microenvironment (TME), variability in antigen expression, and immune suppression limit their efficacy. This review addresses these issues, exploring mechanisms of CAR-MΦ action, optimal construct designs, and interactions within the TME. It also delves into the ex vivo manufacturing challenges of CAR-MΦ, discussing autologous and allogeneic sources and the importance of stringent quality control. The potential synergies of integrating CAR-MΦ with existing cancer therapies like checkpoint inhibitors and conventional chemotherapeutics are examined to highlight possible enhanced treatment outcomes. Furthermore, regulatory pathways for CAR-MΦ therapies are scrutinized alongside established protocols for CAR-T cells, identifying unique considerations essential for clinical trials and market approval. Proposed safety monitoring frameworks aim to manage potential adverse events, such as cytokine release syndrome, crucial for patient safety. Consolidating current research and clinical insights, this review seeks to refine CAR-MΦ therapeutic applications, overcome barriers, and suggest future research directions to transition CAR-MΦ therapies from experimental platforms to standard cancer care options.

Mitochondrial Transfer Between Mesenchymal Stem Cells and Cancer Cells.

Mitochondrial transfer (MT) is a biological process that allows a donor cell to horizontally share its own mitochondria with a recipient cell. Mitochondria are highly dynamic membrane-bound sub-cellular organelles prominently involved in the regulation of the cell energy balance, calcium homeostasis, and apoptotic machinery activation. They physiologically undergo fusion and fission processes in response to the cell requirement, with a continuous morphological re-arrangement. This structural and functional plasticity is at the basis of the MT, described in tissue regeneration, cardiac and neurological diseases, as well as in cancer. Here, the MT has been observed in the tumor micro-environment (TME) from the adipose-derived stem cells (ASCs) to the cancer cells, eventually reverting the lack of the mitochondria respiration function, or enhancing their motility and drug resistance. In this chapter, we outline some key protocols for evaluating this exciting phenomenon of MT. These methodological and technical approaches are very important, considering all the limitations that scientists constantly face, especially in this field of the research.

A pan-cancer analysis of EphA family gene expression and its association with prognosis, tumor microenvironment, and therapeutic targets.

Background: Erythropoietin-producing human hepatocellular (Eph) receptors stand out as the most expansive group of receptor tyrosine kinases (RTKs). Accumulating evidence suggests that within this expansive family, the EphA subset is implicated in driving cancer cell progression, proliferation, invasion, and metastasis, making it a promising target for anticancer treatment. Nonetheless, the extent of EphA family involvement across diverse cancers, along with its intricate interplay with immunity and the tumor microenvironment (TME), remains to be fully illuminated. Methods: The relationships between EphA gene expression and patient survival, immunological subtypes, and TME characteristics were investigated based on The Cancer Genome Atlas (TCGA) database. The analyses employed various R packages. Results: A significant difference in expression was identified for most EphA genes when comparing cancer tissues and non-cancer tissues. These genes independently functioned as prognostic factors spanning multiple cancer types. Moreover, a significant correlation surfaced between EphA gene expression and immune subtypes, except for EphA5, EphA6, and EphA8. EphA3 independently influenced the prognosis of papillary renal cell carcinoma (KIRP). This particular gene exhibited links with immune infiltration subtypes and clinicopathologic parameters, holding promise as a valuable biomarker for predicting prognosis and responsiveness to immunotherapy in patients with KIRP. Conclusion: By meticulously scrutinizing the panorama of EphA genes in a spectrum of cancers, this study supplemented a complete map of the effect of EphA family in Pan-cancer and suggested that EphA family may be a potential target for cancer therapy.

M2-type tumor-associated macrophages upregulated PD-L1 expression in cervical cancer via the PI3K/AKT pathway.

BACKGROUND AND PURPOSE: PD-1/PD-L1 inhibitors have become a promising therapy. However, the response rate is lower than 30% in patients with cervical cancer (CC), which is related to immunosuppressive components in tumor microenvironment (TME). Tumor-associated macrophages (TAMs), as one of the most important immune cells, are involved in the formation of tumor suppressive microenvironment. Therefore, it will provide a theoretical basis for curative effect improvement about the regulatory mechanism of TAMs on PD-L1 expression. METHODS: The clinical data and pathological tissues of CC patients were collected, and the expressions of PD-L1, CD68 and CD163 were detected by immunohistochemistry. Bioinformatics was used to analyze the macrophage subtypes involved in PD-L1 regulation. A co-culture model was established to observe the effects of TAMs on the morphology, migration and invasion function of CC cells, and the regulatory mechanism of TAMs on PD-L1. RESULTS: PD-L1 expression on tumor cells could predict the poor prognosis of patients. And there was a strong correlation between PD-L1 expression with CD163+TAMs infiltration. Similarly, PD-L1 expression was associated with M1/M2-type TAMs infiltration in bioinformatics analysis. The results of cell co-culture showed that M1/M2-type TAMs could upregulate PD-L1 expression, especially M2-type TAMs may elevate the PD-L1 expression via PI3K/AKT pathway. Meanwhile, M1/M2-type TAMs can affect the morphological changes, and enhance migration and invasion abilities of CC cells. CONCLUSIONS: PD-L1 expression in tumor cells can be used as a prognostic factor and is closely related to CD163+TAMs infiltration. In addition, M2-type TAMs can upregulate PD-L1 expression in CC cells through PI3K/AKT pathway, enhance the migration and invasion capabilities, and affect the tumor progression.

A pan-cancer analysis unveiling the function of NR4A family genes in tumor immune microenvironment, prognosis, and drug response.

BACKGROUND: NR4A family genes play crucial roles in cancers. However, the role of NR4A family genes in cancers remains paradoxical as they promote or suppress tumorigenesis. OBJECTIVE: We aimed to conduct comprehensive analyses of the association between the expression of NR4A family genes and tumor microenvironment (TME) based on bioinformatics methods. METHODS: We collected RNA-seq data from 33 cancer types and 20 normal tissue sites from the TCGA and GTEx databases. Expression patterns of NR4A family genes and their associations with DNA methylation, miRNA, overall survival, drug responses, and tumor microenvironment were investigated. RESULTS: Significant downregulation of all NR4A family genes was observed in 15 cancer types. DNA promoter methylation and expression of NR4A family genes were negatively correlated in five cancers. The expression of 10 miRNAs targeting NR4A family genes was negatively correlated with the expression of NR4A family genes. High expression of all NR4A family genes was associated with poor prognosis in stomach adenocarcinoma and increased expressions of NR4A2 and NR4A3 were associated with poor prognosis in adrenocortical carcinoma. In addition, we found an elevated expression of NR4A2, which enhances the response to various chemotherapeutic drugs, whereas NR4A3 decreases drug sensitivity. Interestingly, in breast cancer, NR4A3 was significantly associated with C2 (IFN-γ dominant), C3 (inflammatory), and C6 (TGF-ß dominant) immune subtypes and infiltrated immune cell types, implying both oncogenic and tumor-suppressive functions of NR4A3 in breast cancer. CONCLUSION: The NR4A family genes have the potential to serve as a diagnostic, prognostic, and immunological marker of human cancers.

Neuroinflammation in Glioblastoma: Progress and Perspectives.

Glioblastoma is the most common and malignant primary brain tumor, with high morbidity and mortality. Despite an aggressive, multimodal treatment regimen, including surgical resection followed by chemotherapy and radiotherapy, the prognosis of glioblastoma patients remains poor. One formidable challenge to advancing glioblastoma therapy is the complexity of the tumor microenvironment. The tumor microenvironment of glioblastoma is a highly dynamic and heterogeneous system that consists of not only cancerous cells but also various resident or infiltrating inflammatory cells. These inflammatory cells not only provide a unique tumor environment for glioblastoma cells to develop and grow but also play important roles in regulating tumor aggressiveness and treatment resistance. Targeting the tumor microenvironment, especially neuroinflammation, has increasingly been recognized as a novel therapeutic approach in glioblastoma. In this review, we discuss the components of the tumor microenvironment in glioblastoma, focusing on neuroinflammation. We discuss the interactions between different tumor microenvironment components as well as their functions in regulating glioblastoma pathogenesis and progression. We will also discuss the anti-tumor microenvironment interventions that can be employed as potential therapeutic targets.

Exploring the Role of Neutrophil-Related Genes in Osteosarcoma via an Integrative Analysis of Single-Cell and Bulk Transcriptome.

BACKGROUND: The involvement of neutrophil-related genes (NRGs) in patients with osteosarcoma (OS) has not been adequately explored. In this study, we aimed to examine the association between NRGs and the prognosis as well as the tumor microenvironment of OS. METHODS: The OS data were obtained from the TARGET-OS and GEO database. Initially, we extracted NRGs by intersecting 538 NRGs from single-cell RNA sequencing (scRNA-seq) data between aneuploid and diploid groups, as well as 161 up-regulated differentially expressed genes (DEGs) from the TARGET-OS datasets. Subsequently, we conducted Least Absolute Shrinkage and Selection Operator (Lasso) analyses to identify the hub genes for constructing the NRG-score and NRG-signature. To assess the prognostic value of the NRG signatures in OS, we performed Kaplan-Meier analysis and generated time-dependent receiver operating characteristic (ROC) curves. Gene enrichment analysis (GSEA) and gene set variation analysis (GSVA) were utilized to ascertain the presence of tumor immune microenvironments (TIMEs) and immunomodulators (IMs). Additionally, the KEGG neutrophil signaling pathway was evaluated using ssGSEA. Subsequently, PCR and IHC were conducted to validate the expression of hub genes and transcription factors (TFs) in K7M2-induced OS mice. RESULTS: FCER1G and C3AR1 have been identified as prognostic biomarkers for overall survival. The findings indicate a significantly improved prognosis for OS patients. The effectiveness and precision of the NRG signature in prognosticating OS patients were validated through survival ROC curves and an external validation dataset. The results clearly demonstrate that patients with elevated NRG scores exhibit decreased levels of immunomodulators, stromal score, immune score, ESTIMATE score, and infiltrating immune cell populations. Furthermore, our findings substantiate the potential role of SPI1 as a transcription factor in the regulation of the two central genes involved in osteosarcoma development. Moreover, our analysis unveiled a significant correlation and activation of the KEGG neutrophil signaling pathway with FCER1G and C3AR1. Notably, PCR and IHC demonstrated a significantly higher expression of C3AR1, FCER1G, and SPI1 in Balb/c mice induced with K7M2. CONCLUSIONS: Our research emphasizes the significant contribution of neutrophils within the TIME of osteosarcoma. The newly developed NRG signature could serve as a good instrument for evaluating the prognosis and therapeutic approach for OS.

The impact of tertiary lymphoid structures on tumor prognosis and the immune microenvironment in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a common malignancy whose prognosis and treatment outcome are influenced by many factors. Some studies have found that tertiary lymphoid structures (TLSs) in cancer may contribute to prognosis and the prediction of immunotherapy efficacy However, the combined role of TLSs in NSCLC remains unclear. We accessed The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to obtain mRNA sequencing data and clinical information as the TCGA cohort, and used our own sample of 53 advanced NSCLC as a study cohort. The samples were divided into TLS+ and TLS- groups by pathological tissue sections. Patients of the TLS+ group had a better OS (p = 0.022), PFS (p = 0.042), and DSS (p = 0.004) in the TCGA cohort, and the results were confirmed by the study cohort (PFS, p = 0.012). Furthermore, our result showed that the count and size of TLSs are closely associated with the efficacy of immunotherapy. In addition, the TLS+ group was associated with better immune status and lower tumor mutation load. In the tumor microenvironment (TME), the expression levels of CD4+ T cells and CD8+ T cells of different phenotypes were associated with TLSs. Overall, TLSs are a strong predictor of survival and immunotherapeutic efficacy in advanced NSCLC, and T cell-rich TLSs suggest a more ordered and active immune response site, which aids in the decision-making and application of immunotherapy in the clinic.

Heterogeneity of fibroblast activation protein expression in the microenvironment of an intracranial tumor cohort: head-to-head comparison of gallium-68 FAP inhibitor-04 (68Ga-FAPi-04) and fluoride-18 fluoroethyl-L-tyrosine (18F-FET) in positron emission tomography-computed tomography imaging.

Background: Cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) can interact with tumor parenchymal cells to promote tumor growth and migration. Fibroblast activation protein (FAP) expressed by CAFs can be targeted with positron emission tomography (PET) tracers, but studies on FAP expression patterns in intracranial tumors remain scarce. We aimed to evaluate FAP expression patterns in intracranial tumors with gallium-68 FAP inhibitor-04 (68Ga-FAPi-04) and immunohistochemical staining and to observe the interactions between CAFs and tumor cells with a head-to-head comparison of 68Ga-FAPi-04 and fluoride-18 fluoroethyl-L-tyrosine (18F-FET) for PET quantification analysis. Methods: We prospectively enrolled 22 adult patients with intracranial mass lesions. 68Ga-FAPi-04 and 18F-FET PET-computed tomography (PET/CT) brain imaging were applied before surgery. Maximal tumor-to-brain ratio (TBRmax), metabolic tumor volume (MTV), and total lesion tracer uptake (TLU) was obtained, and different thresholds were used for 68Ga-FAPi-04-positive lesion delineation owing to the lack of relevant guidelines. The MTV and TLU ratios of both tracers were calculated. Linear regression was applied to observe the differential efficacy of semiquantitative PET parameters. Results: A total of 22 patients with a mean age of 50±13 years (range, 27-69 years) were enrolled. Heterogeneous patterns of 68Ga-FAPi-04 uptake [median of maximal standardized uptake value (SUVmax) =3.8; range, 0.1-19.1] were found. More malignant tumors, including brain metastasis, glioblastoma, and medulloblastoma, generally exhibited more significant 68Ga-FAPi-04 uptake than did the less malignant tumors, while the SUVmax and TBRmax exhibited nonsignificant differences across three intracranial lesion groups of primary brain tumor, brain metastasis, and noncancerous disease (SUVmax: P=0.092; TBRmax: P=0.189). Immunohistochemistry staining showed different stromal FAP expression status in various intracranial lesions. In 15 patients with positive 68Ga-FAPi-04 intracranial tumor uptake, the MTVFAPi:MTVFET ratio had differential efficacy in various types of intracranial tumors [95% confidence interval (CI): 0.572-7.712; P=0.027], and further quantification analyses confirmed the differential ability of the MTVFAPi:MTVFET ratio (95% CI: -0.045 to 11.013, P=0.052; 95% CI: 0.044-17.903, P=0.049; 95% CI: -1.131 to 30.596, P=0.065) with different isocontour volumetric thresholds. Conclusions: This head-to-head study demonstrated heterogeneous FAP expression in intracranial tumors. The FAP expression volume percentage in tumor parenchyma may therefore offer benefit with respect to differentiating between intracranial tumor types.

A comprehensive pan-cancer analysis revealing SPAG6 as a novel diagnostic, prognostic and immunological biomarker in tumor.

Background: There have been studies on the role of sperm-associated antigen 6 (SPAG6) in cytoskeleton formation and growth cone stability, but it is also unknown how spag6 affect tumor growth and development. The aim of this study was to clarify the role of SPAG6 in pan-cancer, with some findings about thyroid carcinoma (THCA) validated through experiments. Methods: We examined the role of SPAG6 in pan-cancer, with the data being collected from databases. Further analysis was conducted to assess its correlations with prognosis, gene heterogeneity, stemness, and tumor immunity. The interacting proteins of SPAG6 were also identified, and gene ontology enrichment analysis was performed to determine its biological function. We preliminarily confirmed the role of SPAG6 via in vitro experiments and immunofluorescence staining. Results: This study found that SPAG6 expression was differentially expressed in cancers and at various tumor stages and grades. In stomach and esophageal carcinoma (STES), stomach adenocarcinoma (STAD), kidney renal clear cell carcinoma (KIRC), lung squamous cell carcinoma (LUSC), and adrenocortical carcinoma (ACC), SPAG6 expression was correlated with gender. SPAG6 expression was also found to be correlated with prognostic value, with low expression being associated with poor prognosis. Furthermore, SPAG6 expression was positively linked with immune-related cells in HNSC, chemokine receptors in LUSC, and immune checkpoint genes in THCA. Furthermore, SPAG6 overexpression suppressed the malignant phenotypes of THCA cells, manifested by slower proliferation and decreased migration. The different SPAG6 expression in THCA led to different malignant phenotypes, which are involved in the upregulation of DNA repair, MYC targets, peroxisome, and G2M checkpoint. Conclusions: SPAG6 plays a significant role as an oncogene and can be used as a marker to predict the prognosis of cancer. SPAG6 influences both the tumor immune infiltration and microenvironment, making it a promising immunotherapeutic target for tumor therapy.

Cuproptosis, the novel type of oxidation-induced cell death in thoracic cancers: can it enhance the success of immunotherapy?

Copper is an important metal micronutrient, required for the balanced growth and normal physiological functions of human organism. Copper-related toxicity and dysbalanced metabolism were associated with the disruption of intracellular respiration and the development of various diseases, including cancer. Notably, copper-induced cell death was defined as cuproptosis which was also observed in malignant cells, representing an attractive anti-cancer instrument. Excess of intracellular copper leads to the aggregation of lipoylation proteins and toxic stress, ultimately resulting in the activation of cell death. Differential expression of cuproptosis-related genes was detected in normal and malignant tissues. Cuproptosis-related genes were also linked to the regulation of oxidative stress, immune cell responses, and composition of tumor microenvironment. Activation of cuproptosis was associated with increased expression of redox-metabolism-regulating genes, such as ferredoxin 1 (FDX1), lipoic acid synthetase (LIAS), lipoyltransferase 1 (LIPT1), dihydrolipoamide dehydrogenase (DLD), drolipoamide S-acetyltransferase (DLAT), pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), and pyruvate dehydrogenase E1 subunit beta (PDHB)). Accordingly, copper-activated network was suggested as an attractive target in cancer therapy. Mechanisms of cuproptosis and regulation of cuproptosis-related genes in different cancers and tumor microenvironment are discussed in this study. The analysis of current findings indicates that therapeutic regulation of copper signaling, and activation of cuproptosis-related targets may provide an effective tool for the improvement of immunotherapy regimens.

Decoding the spatiotemporal heterogeneity of tumor-associated macrophages.

Tumor-associated macrophages (TAMs) are pivotal in cancer progression, influencing tumor growth, angiogenesis, and immune evasion. This review explores the spatial and temporal heterogeneity of TAMs within the tumor microenvironment (TME), highlighting their diverse subtypes, origins, and functions. Advanced technologies such as single-cell sequencing and spatial multi-omics have elucidated the intricate interactions between TAMs and other TME components, revealing the mechanisms behind their recruitment, polarization, and distribution. Key findings demonstrate that TAMs support tumor vascularization, promote epithelial-mesenchymal transition (EMT), and modulate extracellular matrix (ECM) remodeling, etc., thereby enhancing tumor invasiveness and metastasis. Understanding these complex dynamics offers new therapeutic targets for disrupting TAM-mediated pathways and overcoming drug resistance. This review underscores the potential of targeting TAMs to develop innovative cancer therapies, emphasizing the need for further research into their spatial characteristics and functional roles within the TME.

CAR-T cell technologies that interact with the tumour microenvironment in solid tumours.

INTRODUCTION: Chimeric antigen receptor (CAR) T-cells have emerged as a ground-breaking therapy for the treatment of hematological malignancies due to their capacity for rapid tumor-specific killing and long-lasting tumor immunity. However, the same success has not been observed in patients with solid tumors. Largely, this is due to the additional challenges imposed by safe and uniform target selection, inefficient CAR T-cell access to sites of disease and the presence of a hostile immunosuppressive tumor microenvironment. AREAS COVERED: Literature was reviewed on the PubMed database from the first description of a CAR by Kuwana, Kurosawa and colleagues in December 1987 through to the present day. This literature indicates that in order to tackle solid tumors, CAR T-cells can be further engineered with additional armoring strategies that facilitate trafficking to and infiltration of malignant lesions together with reversal of suppressive immune checkpoints that operate within solid tumor lesions. EXPERT OPINION: In this review, we describe a number of recent advances in CAR T-cell technology that set out to combat the problems imposed by solid tumors including tumor recruitment, infiltration, immunosuppression, metabolic compromise, and hypoxia.

Extracellular Matrix Sulfation in the Tumor Microenvironment Stimulates Cancer Stemness and Invasiveness.

Tumor extracellular matrices (ECM) exhibit aberrant changes in composition and mechanics compared to normal tissues. Proteoglycans (PG) are vital regulators of cellular signaling in the ECM with the ability to modulate receptor tyrosine kinase (RTK) activation via their sulfated glycosaminoglycan (sGAG) side chains. However, their role on tumor cell behavior is controversial. Here, it is demonstrated that PGs are heavily expressed in lung adenocarcinoma (LUAD) patients in correlation with invasive phenotype and poor prognosis. A bioengineered human lung tumor model that recapitulates the increase of sGAGs in tumors in an organotypic matrix with independent control of stiffness, viscoelasticity, ligand density, and porosity, is developed. This model reveals that increased sulfation stimulates extensive proliferation, epithelial-mesenchymal transition (EMT), and stemness in cancer cells. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase (PI3K) signaling axis is identified as a mediator of sulfation-induced molecular changes in cells upon activation of a distinct set of RTKs within tumor-mimetic hydrogels. The study shows that the transcriptomic landscape of tumor cells in response to increased sulfation resembles native PG-rich patient tumors by employing integrative omics and network modeling approaches.

Targeting anticancer immunity in melanoma tumour microenvironment: unleashing the potential of adjuvants, drugs, and phytochemicals.

Melanoma poses a challenge in oncology because of its aggressive nature and limited treatment modalities. The tumour microenvironment (TME) in melanoma contains unique properties such as an immunosuppressive and high-density environment, unusual vasculature, and a high number of stromal and immunosuppressive cells. In recent years, numerous experiments have focused on boosting the immune system to effectively remove malignant cells. Adjuvants, consisting of phytochemicals, toll-like receptor (TLR) agonists, and cytokines, have shown encouraging results in triggering antitumor immunity and augmenting the therapeutic effectiveness of anticancer therapy. These adjuvants can stimulate the maturation of dendritic cells (DCs) and infiltration of cytotoxic CD8+ T lymphocytes (CTLs). Furthermore, nanocarriers can help to deliver immunomodulators and antigens directly to the tumour stroma, thereby improving their efficacy against malignant cells. The remodelling of melanoma TME utilising phytochemicals, agonists, and other adjuvants can be combined with current modalities for improving therapy outcomes. This review article explores the potential of adjuvants, drugs, and their nanoformulations in enhancing the anticancer potency of macrophages, CTLs, and natural killer (NK) cells. Additionally, the capacity of these agents to repress the function of immunosuppressive components of melanoma TME, such as immunosuppressive subsets of macrophages, stromal and myeloid cells will be discussed.

A pan-cancer analysis of the core pre-mRNA 3' end processing factors, and their association with prognosis, tumor microenvironment, and potential targets.

Alternative polyadenylation (APA) is a crucial mechanism for regulating gene expression during pre-mRNA 3' processing. Pre-mRNA 3' end processing factors is the main factor involved in this process. However, pre-mRNA 3' end processing factors in different cancer expression profiles and the relationship between pre-mRNA 3' end processing factors and tumor microenvironment and the prognosis of the same patient is still unclear. In this study, we conducted a comprehensive exploration of the core pre-mRNA 3' end processing factors across various cancer types by utilizing common cancer database, and revealing a robust correlation between the expression of these core factors and tumor characteristics. Leveraging advanced bioinformatics databases, we evaluated the expression levels and prognostic relevance of pre-mRNA 3' end processing factors across pan-cancer tissues. Our extensive pan-cancer analysis revealed unique expression patterns of pre-mRNA 3' end processing factors in both tumor and adjacent non-tumorous tissues. Notably, we found a significant correlation between the expression levels of pre-mRNA 3' end processing factors and patient prognosis. Furthermore, we identified strong associations between pre-mRNA 3' end processing factors expression and various factors, such as stromal, immune, RNA stemness, and DNA stemness scores across pan-cancer tissues. Our data also highlighted a link between the expression of pre-mRNA 3' end processing factors and sensitivity to specific drugs, including pyrazoloacndine, amonaflide, and chelerythrinede, among others. We found four key pre-mRNA 3' end processing factors that play a crucial role in mRNA preprocessing. Our study illuminates the potential promotion and inhibition role of pre-mRNA 3' end processing regulators in the progression of cancer, CPSF2, CPSF3, CSTF2, SYMPK offering valuable insights for future research investigations on these regulators as diagnostic markers and therapeutic targets across pan-cancer.

M1-polarized macrophage-derived cellular nanovesicle-coated lipid nanoparticles for enhanced cancer treatment through hybridization of gene therapy and cancer immunotherapy.

Optimum genetic delivery for modulating target genes to diseased tissue is a major obstacle for profitable gene therapy. Lipid nanoparticles (LNPs), considered a prospective vehicle for nucleic acid delivery, have demonstrated efficacy in human use during the COVID-19 pandemic. This study introduces a novel biomaterial-based platform, M1-polarized macrophage-derived cellular nanovesicle-coated LNPs (M1-C-LNPs), specifically engineered for a combined gene-immunotherapy approach against solid tumor. The dual-function system of M1-C-LNPs encapsulates Bcl2-targeting siRNA within LNPs and immune-modulating cytokines within M1 macrophage-derived cellular nanovesicles (M1-NVs), effectively facilitating apoptosis in cancer cells without impacting T and NK cells, which activate the intratumoral immune response to promote granule-mediating killing for solid tumor eradication. Enhanced retention within tumor was observed upon intratumoral administration of M1-C-LNPs, owing to the presence of adhesion molecules on M1-NVs, thereby contributing to superior tumor growth inhibition. These findings represent a promising strategy for the development of targeted and effective nanoparticle-based cancer genetic-immunotherapy, with significant implications for advancing biomaterial use in cancer therapeutics.

Components, Formulations, Deliveries, and Combinations of Tumor Vaccines.

Tumor vaccines, an important part of immunotherapy, prevent cancer or kill existing tumor cells by activating or restoring the body's own immune system. Currently, various formulations of tumor vaccines have been developed, including cell vaccines, tumor cell membrane vaccines, tumor DNA vaccines, tumor mRNA vaccines, tumor polypeptide vaccines, virus-vectored tumor vaccines, and tumor-in-situ vaccines. There are also multiple delivery systems for tumor vaccines, such as liposomes, cell membrane vesicles, viruses, exosomes, and emulsions. In addition, to decrease the risk of tumor immune escape and immune tolerance that may exist with a single tumor vaccine, combination therapy of tumor vaccines with radiotherapy, chemotherapy, immune checkpoint inhibitors, cytokines, CAR-T therapy, or photoimmunotherapy is an effective strategy. Given the critical role of tumor vaccines in immunotherapy, here, we look back to the history of tumor vaccines, and we discuss the antigens, adjuvants, formulations, delivery systems, mechanisms, combination therapy, and future directions of tumor vaccines.

Lactic acid: a narrative review of a promoter of the liver cancer microenvironment.

Background and Objective: Lactic acid is a metabolite of glycolysis produced in the body, and its production is thought to be a mechanism by which cancer cells evade immune surveillance. Immune evasion and metabolic changes are well established as basic hallmarks of cancer. Although lactate has long been considered a waste product, it is now generally recognized to be a versatile small-molecule chemical that plays an important part in the tumor microenvironment (TME), with increased lactate production linked to the development of human malignancies. Metabolism in liver cancer is redirected toward glycolysis, which enhances the production of metabolic compounds used by tumor cells to produce proteins, lipids, and nucleotides, enabling them to maintain high proliferation rates and to establish the TME. Dysregulation of metabolic activity in liver cancer may impair antitumor responses owing to the immunosuppressive activity of the lactate produced by anaerobic glycolytic rates in tumor cells. This review primarily explores the link connection between lactic acid and the TME; evaluates the role of lactic acid in the occurrence, metastasis, prognosis, and treatment of liver cancer. Additionally, it investigates the associated pathways as potential targets for liver cancer treatment. Methods: Literature searches were conducted in PubMed, Web of Science, and Google Scholar, with the publication date of the most recent article included being January 2024. After eliminating duplicate articles and less relevant articles through titles and abstracts, we selected 113 articles for this review. We categorized references into two categories. One is to classify the content into lactate-related, liver cancer-related and tumor metabolism-related. The other is to classify the article types, which are divided into reviews, research articles and clinical trials. Additionally, we consulted the reference lists of the relevant articles to ensure coverage was comprehensive and unbiased. Key Content and Findings: The connection between lactic acid and the TME has recently become an area of intense research interest, and many related articles have been published in this field. The main finding of this review is to summarize the proven link between lactate and the TME and its possible impact on the TME of liver cancer. And analyzed the potential of lactate in liver cancer treatment and prognosis prediction. Conclusions: Lactate may be key to developing novel approaches in the future treatment of liver cancer. Related research on the combination of classic therapies and molecular targeted drugs may provide innovative medicines that more selectively regulate immune cell activity.