Roles of tumor-associated macrophages in anti-PD-1/PD-L1 immunotherapy for solid cancers.

In recent years, tumor immunotherapy has made significant progress. However, tumor immunotherapy, particularly immune checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitors), benefits only a tiny proportion of patients in solid cancers. The tumor microenvironment (TME) acts a significant role in tumor immunotherapy. Studies reported that tumor-associated macrophages (TAMs), as one of the main components of TME, seriously affected the therapeutic effect of PD-1/PD-L1 inhibitors. In this review, we analyzed TAMs from epigenetic and single-cell perspectives and introduced the role and mechanisms of TAMs in anti-programmed death protein 1(anti-PD-1) therapy. In addition, we summarized combination regimens that enhance the efficacy of tumor PD-1/PD-L1 inhibitors and elaborated on the role of the TAMs in different solid cancers. Eventually, the clinical value of TAMs by influencing the therapeutic effect of tumor PD-1/PD-L1 inhibitors was discussed. These above are beneficial to elucidate poor therapeutic effect of PD-1/PD-L1 inhibitors in solid tumors from the point of view of TAMs and explore the strategies to improve its objective remission rate of solid cancers.

Extracellular vesicles remodel tumor environment for cancer immunotherapy.

Tumor immunotherapy has transformed neoplastic disease management, yet low response rates and immune complications persist as major challenges. Extracellular vesicles including exosomes have emerged as therapeutic agents actively involved in a diverse range of pathological conditions. Mounting evidence suggests that alterations in the quantity and composition of extracellular vesicles (EVs) contribute to the remodeling of the immune-suppressive tumor microenvironment (TME), thereby influencing the efficacy of immunotherapy. This revelation has sparked clinical interest in utilizing EVs for immune sensitization. In this perspective article, we present a comprehensive overview of the origins, generation, and interplay among various components of EVs within the TME. Furthermore, we discuss the pivotal role of EVs in reshaping the TME during tumorigenesis and their specific cargo, such as PD-1 and non-coding RNA, which influence the phenotypes of critical immune cells within the TME. Additionally, we summarize the applications of EVs in different anti-tumor therapies, the latest advancements in engineering EVs for cancer immunotherapy, and the challenges encountered in clinical translation. In light of these findings, we advocate for a broader understanding of the impact of EVs on the TME, as this will unveil overlooked therapeutic vulnerabilities and potentially enhance the efficacy of existing cancer immunotherapies.

Multifunctional CaCO3@Cur@QTX125@HA nanoparticles for effectively inhibiting growth of colorectal cancer cells.

Colorectal cancer (CRC) is a major cause of cancer-related deaths in humans, and effective treatments are still needed in clinical practice. Despite significant developments in anticancer drugs and inhibitors, their poor stability, water solubility, and cellular membrane permeability limit their therapeutic efficacy. To address these issues, multifunctional CaCO3 nanoparticles loaded with Curcumin (Cur) and protein deacetylase (HDAC) inhibitor QTX125, and coated with hyaluronic acid (HA) (CaCO3@Cur@QTX125@HA), were prepared through a one-step gas diffusion strategy. Dynamic light scattering (DLS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) showed that CaCO3@Cur@QTX125@HA nanoparticles have uniform spherical morphology and elemental distribution, with diameters around 450 nm and a Zeta potential of - 8.11 mV. The controlled release of Cur from the nanoparticles was observed over time periods of 48 h. Cellular uptake showed that CaCO3@Cur@QTX125@HA nanoparticles were efficiently taken up by cancer cells and significantly inhibited their growth. Importantly, CaCO3@Cur@QTX125@HA nanoparticles showed specific inhibitory effects on CRC cell growth. Encouragingly, CaCO3@Cur@QTX125@HA nanoparticles successfully internalized into CRC patient-derived organoid (PDO) models and induced apoptosis of tumor cells. The multifunctional CaCO3@Cur@QTX125@HA nanoparticles hold promise for the treatment of CRC.

Exosomal circPOLQ promotes macrophage M2 polarization via activating IL-10/STAT3 axis in a colorectal cancer model.

BACKGROUND: Accumulating evidence demonstrates that an increased tumor-associated macrophage abundance is often associated with poor prognosis in colorectal cancer (CRC). The mechanism underlying the effect of tumor-derived exosomes on M2 macrophage polarization remains elusive. RESULTS: The novel circular RNA circPOLQ exhibited significantly higher expression in CRC tissues than in paired normal tissues. Higher circPOLQ expression was associated with poorer prognosis in patients with CRC. In vitro and in vivo experiments showed that tumor-derived exosomal circPOLQ did not directly regulate CRC cell development but promoted CRC metastatic nodule formation by enhancing M2 macrophage polarization. circPOLQ activated the interleukin-10/signal transducer and activator of transcription 3 axis by targeting miR-379-3 p to promote M2 macrophage polarization. CONCLUSION: circPOLQ can enter macrophages via CRC cell-derived exosomes and promote CRC metastatic nodule formation by enhancing M2 macrophage polarization. These findings reveal a tumor-derived exosome-mediated tumor-macrophage interaction potentially affecting CRC metastatic nodule formation.

YTHDF2-mediated circYAP1 drives immune escape and cancer progression through activating YAP1/TCF4-PD-L1 axis.

Immune escape is identified as one of the reasons for the poor prognosis of colorectal cancer (CRC) patients. Circular RNAs are considered to promote tumor progression by mediating tumor immune escape. We discovered that higher expression of circYAP1 was associated with a worse prognosis of CRC patients. Functional experiments in vitro and in vivo showed that circYAP1 upregulation inhibited the cytotoxicity of CD8+ T cells by upregulating programmed death ligand-1 (PD-L1). Mechanistically, we found that circYAP1 directly binds to the YAP1 protein to prevent its phosphorylation, enhancing proportion of YAP1 protein in the nucleus, and that YAP1 interacts with TCF4 to target the PD-L1 promoter and initiate PD-L1 transcription in CRC cells. Taken together, circYAP1 promotes CRC immune escape and tumor progression by activating the YAP1/TCF4-PD-L1 axis and may provide a new strategy for combination immunotherapy of CRC patients.

Engineered exosomes from different sources for cancer-targeted therapy.

Exosome is a subgroup of extracellular vesicles, which has been serving as an efficient therapeutic tool for various diseases. Engineered exosomes are the sort of exosomes modified with surface decoration and internal therapeutic molecules. After appropriate modification, engineered exosomes are able to deliver antitumor drugs to tumor sites efficiently and precisely with fewer treatment-related adverse effects. However, there still exist many challenges for the clinical translation of engineered exosomes. For instance, what sources and modification strategies could endow exosomes with the most efficient antitumor activity is still poorly understood. Additionally, how to choose appropriately engineered exosomes in different antitumor therapies is another unresolved problem. In this review, we summarized the characteristics of engineered exosomes, especially the spatial and temporal properties. Additionally, we concluded the recent advances in engineered exosomes in the cancer fields, including the sources, isolation technologies, modification strategies, and labeling and imaging methods of engineered exosomes. Furthermore, the applications of engineered exosomes in different antitumor therapies were summarized, such as photodynamic therapy, gene therapy, and immunotherapy. Consequently, the above provides the cancer researchers in this community with the latest ideas on engineered exosome modification and new direction of new drug development, which is prospective to accelerate the clinical translation of engineered exosomes for cancer-targeted therapy.

Radiotherapy remodels the tumor microenvironment for enhancing immunotherapeutic sensitivity.

Cancer immunotherapy has transformed traditional treatments, with immune checkpoint blockade being particularly prominent. However, immunotherapy has minimal benefit for patients in most types of cancer and is largely ineffective in some cancers (such as pancreatic cancer and glioma). A synergistic anti-tumor response may be produced through the combined application with traditional tumor treatment methods. Radiotherapy (RT) not only kills tumor cells but also triggers the pro-inflammatory molecules' release and immune cell infiltration, which remodel the tumor microenvironment (TME). Therefore, the combination of RT and immunotherapy is expected to achieve improved efficacy. In this review, we summarize the effects of RT on cellular components of the TME, including T cell receptor repertoires, different T cell subsets, metabolism, tumor-associated macrophages and other myeloid cells (dendritic cells, myeloid-derived suppressor cells, neutrophils and eosinophils). Meanwhile, non-cellular components such as lactate and extracellular vesicles are also elaborated. In addition, we discuss the impact of different RT modalities on tumor immunity and issues related to the clinical practice of combination therapy.

Roles of the Exosomes Derived From Myeloid-Derived Suppressor Cells in Tumor Immunity and Cancer Progression.

Tumor immunity is involved in malignant tumor progression. Myeloid-derived suppressor cells (MDSCs) play an irreplaceable role in tumor immunity. MDSCs are composed of immature myeloid cells and exhibit obvious immunomodulatory functions. Exosomes released by MDSCs (MDSCs-Exos) have similar effects to parental MDSCs in regulating tumor immunity. In this review, we provided a comprehensive description of the characteristics, functions and mechanisms of exosomes. We analyzed the immunosuppressive, angiogenesis and metastatic effects of MDSCs-Exos in different tumors through multiple perspectives. Immunotherapy targeting MDSCs-Exos has demonstrated great potential in cancers and non-cancerous diseases.

Effect of CRISPR/Cas9-Edited PD-1/PD-L1 on Tumor Immunity and Immunotherapy.

Clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease9 (CRISPR/Cas9) gene editing technology implements precise programming of the human genome through RNA guidance. At present, it has been widely used in the construction of animal tumor models, the study of drug resistance regulation mechanisms, epigenetic control and innovation in cancer treatment. Tumor immunotherapy restores the normal antitumor immune response by restarting and maintaining the tumor-immune cycle. CRISPR/Cas9 technology has occupied a central position in further optimizing anti-programmed cell death 1(PD-1) tumor immunotherapy. In this review, we summarize the recent progress in exploring the regulatory mechanism of tumor immune PD-1 and programmed death ligand 1(PD-L1) based on CRISPR/Cas9 technology and its clinical application in different cancer types. In addition, CRISPR genome-wide screening identifies new drug targets and biomarkers to identify potentially sensitive populations for anti-PD-1/PD-L1 therapy and maximize antitumor effects. Finally, the strong potential and challenges of CRISPR/Cas9 for future clinical applications are discussed.

Roles of exosomal circRNAs in tumour immunity and cancer progression.

Tumour immunity plays an important role in the development of cancer. Tumour immunotherapy is an important component of antitumour therapy. Exosomes, a type of extracellular vesicle, act as mediators of intercellular communication and molecular transfer and play an essential role in tumour immunity. Circular RNAs (circRNAs) are a new type of noncoding RNA that are enriched within exosomes. In this review, we describe the effects of exosomal circRNAs on various immune cells and the mechanisms of these effects, including macrophages, neutrophils, T cells, and Natural killer (NK) cells. Next, we elaborate on the latest progress of exosome extraction. In addition, the function of exosomal circRNAs as a potential prognostic and drug sensitivity marker is described. We present the great promise of exosomal circRNAs in regulating tumour immunity, predicting patient outcomes, and evaluating drug efficacy.

Exosome-derived noncoding RNAs: Function, mechanism, and application in tumor angiogenesis.

Exosomes are extracellular vesicles released by various cell types that perform various biological functions, mainly mediating communication between different cells, especially those active in cancer. Noncoding RNAs (ncRNAs), of which there are many types, were recently identified as enriched and stable in the exocrine region and play various roles in the occurrence and progression of cancer. Abnormal angiogenesis has been confirmed to be related to human cancer. An increasing number of studies have shown that exosome-derived ncRNAs play an important role in tumor angiogenesis. In this review, we briefly outline the characteristics of exosomes, ncRNAs, and tumor angiogenesis. Then, the mechanism of the impact of exosome-derived ncRNAs on tumor angiogenesis is analyzed from various angles. In addition, we focus on the regulatory role of exosome-derived ncRNAs in angiogenesis in different types of cancer. Furthermore, we emphasize the potential role of exosome-derived ncRNAs as biomarkers in cancer diagnosis and prognosis and therapeutic targets in the treatment of tumors.

Derivation and Clinical Validation of a Redox-Driven Prognostic Signature for Colorectal Cancer.

Colorectal cancer (CRC), a seriously threat that endangers public health, has a striking tendency to relapse and metastasize. Redox-related signaling pathways have recently been extensively studied in cancers. However, the study and potential role of redox in CRC remain unelucidated. We developed and validated a risk model for prognosis and recurrence prediction in CRC patients via identifying gene signatures driven by redox-related signaling pathways. The redox-driven prognostic signature (RDPS) was demonstrated to be an independent risk factor for patient survival (including OS and RFS) in four public cohorts and one clinical in-house cohort. Additionally, there was an intimate association between the risk score and tumor immune infiltration, with higher risk score accompanied with less immune cell infiltration. In this study, we used redox-related factors as an entry point, which may provide a broader perspective for prognosis prediction in CRC and have the potential to provide more promising evidence for immunotherapy.

LINC01272/miR-876/ITGB2 axis facilitates the metastasis of colorectal cancer via epithelial-mesenchymal transition.

Background: At the time of diagnosis, colorectal cancer (CRC) patients are usually in an advanced stage of disease, which is accompanied by metastasis. Long noncoding RNAs (lncRNAs) play critical regulatory roles in cancer biology. However, the contributions of lncRNA LINC01272 to CRC remain elusive. Methods: Bioinformatics and the survminer R package were used to predict intermolecular correlations and prognostic indicators. Quantitative real-time PCR was used to examine molecular expression. In vitro experiments, including migration assays, invasion assays, and wound healing assays, were used to investigate the effects of LINC01272, ITGB2 and miR-876 on CRC cell migration and invasion abilities. Furthermore, a dual-luciferase reporter gene assay was performed to explore the potential mechanism by which LINC01272 contributes to CRC. Results: We found that LINC01272 was highly expressed in multiple cancers and closely related to core epithelial-mesenchymal transition (EMT) factors and that high levels of LINC01272 are associated with a poor prognosis in CRC patients. qRT-PCR revealed that LINC01272 was highly expressed and negatively associated with miR-876 in CRC. Additionally, LINC01272 or ITGB2 silencing reduced, while miR-876 overexpression promoted, the invasiveness and metastatic capacity of CRC cells in vitro. Moreover, LINC01272 potentially targeted miR-876, and miR-876 potentially targeted ITGB2. Conclusion: LINC01272 was highly expressed in CRC and predicted a poor prognosis. LINC01272 promoted EMT and metastasis by regulating miR-876/ITGB2 to act as an oncogene in CRC. LINC01272 may be a promising prognostic biomarker and therapeutic target for the treatment of CRC patients in the future.

Effects of Tumor-Derived Exosome Programmed Death Ligand 1 on Tumor Immunity and Clinical Applications.

Programmed death ligand 1 (PD-L1) is a typical immune surface protein that binds to programmed cell death 1 (PD-1) on T cells through its extracellular domain. Subsequently, T cell activity is inhibited, and tumor immune tolerance is enhanced. Anti-PD-1/PD-L1 immune checkpoint therapy blocks the combination of PD-1/PD-L1 and rejuvenates depleted T cells, thereby inhibiting tumor growth. Exosomes are biologically active lipid bilayer nanovesicles secreted by various cell types, which mediate signal communication between cells. Studies have shown that PD-L1 can not only be expressed on the surface of tumor cells, immune cells, and other cells in the tumor microenvironment, but also be released from tumor cells and exist in an extracellular form. In particular, exosome PD-L1 plays an unfavorable role in tumor immunosuppression. The immunomodulatory effect of exosome PD-L1 and its potential in fluid diagnosis have attracted our attention. This review aims to summarize the available evidence regarding the biological characteristics of exosome PD-L1 in tumor immunity, with a particular focus on the mechanisms in different cancers and clinical prospects. In addition, we also summarized the current possible and effective detection methods for exosome PD-L1 and proposed that exosome PD-L1 has the potential to become a target for overcoming anti-PD-1/PD-L1 antibody treatment resistance.

LINC01296/miR-141-3p/ZEB1-ZEB2 axis promotes tumor metastasis via enhancing epithelial-mesenchymal transition process.

Purpose: Tumor metastasis seriously affects the survival of patients. In recent years, some studies confirmed that long non-coding RNA (lncRNA) played an essential role in tumor progression. A few studies reported that LINC01296 acted as an oncogenic regulator of cancer. However, its in-depth specific biological mechanism in tumor metastasis is still unknown. Methods: Real-time quantitative PCR (qPCR) was performed to detect the expression of LINC01296 and miR-141-3p in NSCLC, CRC tissues and cell lines, and the dual luciferase report was used to evaluate the relationship between LINC01296, miR-141-3p and ZEB1/ZEB2 relationship. Western blot experiments are used to detect changes in protein levels. Transwell and wound healing measures migration and invasion capabilities. Results: In this study, we used non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) as the research objects, LINC01296 was found to be highly expressed in NSCLC and CRC tissues and positively related to poor prognosis. We also demonstrated LINC01296 regulated NSCLC and CRC invasion and metastasis by modulating epithelial-mesenchymal transition (EMT) by up-regulating ZEB1 and ZEB2. Consequently, LINC01296 acted as a sponge of miR-141-3p, which negatively regulates EMT process. Conclusions: The report revealed a new mechanism by which LINC01296 regulates the EMT process through miR-141-3p/ZEB1-ZEB2 axis and affects cancer metastasis.

Long noncoding RNA SNHG15 enhances the development of colorectal carcinoma via functioning as a ceRNA through miR-141/SIRT1/Wnt/ß-catenin axis.

Colon cancer, also known as colorectal carcinoma (CRC), remains to be one of the most mainsprings of cancer-produced deaths entire world. We planned to grab the role and possible biological cause of a long noncoding RNA, namely, small nucleolar RNA host gene 15 (SNHG15), in CRC. The mRNA level of SNHG15 in CRC tissues and cells was detected, followed by investigating the impacts of the depression of SNHG15 on CRC cell proliferation (viability and colony-forming), apoptosis, migration, and invasion. Moreover, the association between SNHG15 and miR-141 and the correlation between miR-141 and SIRT1 were also explored. Besides, the influences of dysregulated SNHG15 on the Wnt/ß-catenin signal-related proteins were determined. SNHG15 was highly expressed in CRC tissues and cells. Depression of SNHG15 depressed proliferation, enhanced apoptosis, and repressed the migration and invasion of CRC cells. In addition, SNHG15 presented a downside tendency on regulating miR-141, and the miR-141 inhibitor dramatically changeover the impacts of SNHG15 depression on tumor growth and metastasis. Moreover, SIRT1 was verified as a functional target of miR-141 in CRC cells. Besides, the suppression of SNHG15 remarkably controlled activating the Wnt/ß-catenin signals, which was reversed after inhibiting miR-141 at the same time. The investigated results in this research revealed that the increased expression of SNHG15 may enhance the process of CRC by acting as a ceRNA in regulating SIRT1 expression by sponging miR-141. Thus we propose that Wnt/ß-catenin signals may be a downriver regulator in mediating the impacts of SNHG15 in CRC and SNHG15-miR-141-SIRT1 axis may pave a new sight in explaining the biological processes of CRC.

Distinct prognostic value of dynactin subunit 4 (DCTN4) and diagnostic value of DCTN1, DCTN2, and DCTN4 in colon adenocarcinoma.

BACKGROUND: Colon adenocarcinoma (COAD) is ranked as the third most commonly diagnosed cancer in both women and men, and it is the most frequently occurring malignant tumor. Dynactin is a protein compound based on multiple subunits, including dynactin 1-6 (DCTN1-6), in most categories of cytoplasmic dynein performance in eukaryotes. Nevertheless, correlations between the DCTN family and the prognosis and diagnosis of COAD remain unidentified. METHODS: Statistics for DCTN mRNA expression in patients with COAD were acquired from The Cancer Genome Atlas. Kaplan-Meier analyses and a Cox regression model were applied to determine overall survival, with computation of HRs and 95% CIs. Several online data portals were used to assess the biological process, and pathway examination was performed using the Kyoto Encyclopedia of Genes and Genomes to predict the biological functionality of DCTN genes. RESULTS: We found that high expression of DCTN4 was linked with satisfactory results for overall survival (P=0.042, HR=0.650, 95% CI 0.429-0.985). The expression of DCTN1, DATN2, and DCTN4 was closely correlated with the frequency of colon tumors (P<0.001, area under the curve [AUC]=0.8811, 95% CI 0.8311-0.9312; P<0.001, AUC=0.870, 96% CI 0.833-0.9071; and P=0.0051, AUC=0.6317, 95% CI 0.5725-0.6908, respectively). In the enrichment examination, the level of gene expression was related to the cell cycle, cell apoptosis, and the cell metastasis pathway. CONCLUSION: The expression levels of DCTN1, DCTN2, and DCTN4 could allow differentiation between cancer-bearing tissues and paracancerous tissue. These genes can be applied as biomarkers to predict the prognosis and diagnosis of COAD.