Response In Tumor Microenvironment Research Articles

Ubiquitin-Specific Protease 52 as a Prognostic Biomarker Correlates with Tumor Microenvironment and Therapy Response in Colorectal Cancer.

As the primary members of the deubiquitinase family, ubiquitin-specific proteases can regulate the efficacy of immunotherapy and mediate immune evasion. However, further research is needed to explore the influence of USP52 on the prognosis of colorectal cancer (CRC), the tumor immune microenvironment, and therapeutic response. The differential expression of USP52 between CRC and normal tissues was analyzed using multiple public databases. The relationship between USP52 with the prognosis and clinicopathological characteristics of CRC patients was evaluated, and a nomogram was constructed to predict patient survival based on USP52 expression. Subsequently, gene set variation analysis (GSVA) was used to explore the potential biological functions of USP52 in CRC. The impact of USP52 on the tumor microenvironment (TME) was estimated. Moreover, the effect of USP52 on the response to immunotherapy and chemotherapeutic drugs in CRC was investigated. Finally, the correlation between tumor mutation burden (TMB)/microsatellite instability (MSI) status and USP52 was explored. The expression of USP52 was markedly upregulated in CRC, correlating with a poor prognosis in patients. GSVA uncovered a strong association between high USP52 and immune suppression. Furthermore, high USP52 was found to be correlated with a non-inflamed TME, resulting in reduced immune cell infiltration levels. Additionally, it was observed that patients with high USP52 exhibited low sensitivity to both immunotherapy and chemotherapeutic drugs. Lastly, high USP52 was negatively associated with high TMB and MSI. This study revealed the significance of USP52 in TME, efficacy of therapy, and clinical prognosis in CRC, offering novel insights for the therapeutic advancements in CRC.

Impact of mitochondrial damage on tumor microenvironment and immune response: a comprehensive bibliometric analysis.

Mitochondrial damage contributes to apoptosis, oxidative stress, and inflammation, which collectively impact the immune system's function and the tumor microenvironment (TME). These processes, in turn, influence tumor cell growth, migration, and response to treatment. We conducted a bibliometric analysis to elucidate the complex interactions between mitochondrial damage, the immune system, and the TME. Data were sourced from the Science Citation Index Core Collection (WoSCC) and analyzed using advanced tools like VOSviewer and Citespace. Our focus was on literature published between 1999 and 2023 concerning the interactions between mitochondrial damage and the TME, as well as immune responses to tumors. The analysis included regional contributions, journal influence, institutional collaborations, authorship, co-cited authors, and keyword citation bursts. Our research encompassed 2,039 publications, revealing an increasing trend in annual output exploring the relationship between mitochondrial damage, TME dynamics, and immune responses. China, the United States, and South Korea emerged as the leading contributors. Prominent institutions included Institut National de la Santé et de la Recherche Médicale, University of Texas System, China Medical University, and Sun Yat-sen University. Key journals in this field are the International Journal of Molecular Sciences, Mitochondrion, and the European Journal of Pharmacology. Liang H and Wallace DC were identified as the most productive and co-cited authors, respectively. Keyword analysis highlighted the critical roles of inflammatory responses, oxidative stress, and the immune system in recent research. This bibliometric analysis provides a comprehensive overview of historical and current research trends, underscoring the pivotal role of mitochondrial damage in the TME and immune system.

Tumor Microenvironment‐Activatable Metal‐Phenolic Nanoformulations for Ultrasound‐Boosted Ferroptosis through Triple Regulatory Pathways

AbstractDespite its effectiveness in exterminating tumor cells, ferroptosis is seriously hampered by the high expression of antioxidant glutathione (GSH) and the inadequacy of endogenous H2O2 in tumors. Herein, metal‐phenolic nanoformulations (FNCP NFs) composed of sonosensitizer Chlorin e6 (Ce6), the phenolic GSH consumer naphthazarin, and Fe3+, followed by the modification of PEG2000, are strategically designed and fabricated for ultrasound‐boosted ferroptosis in tumor cells through triple regulatory pathways. The carrier‐free FNCP NFs can rapidly dissociate under tumor microenvironment response with the assistance of ultrasound, releasing Fe2+, Ce6, and naphthazarin. Ce6 and Fe2+ are capable of producing singlet oxygen (1O2) and hydroxyl radicals (·OH) by ultrasound‐activated sonodynamic therapy and Fenton reaction‐mediated chemodynamic therapy (CDT), respectively, which not only induce apoptotic cell death but also lead to the effective accumulation of lipid peroxidation (LPO), resulting in ferroptosis. Meanwhile, the released naphthazarin and the self‐cycling valence alternations of Fe3+/Fe2+ promote the significant decrease of intracellular GSH contents, further inducing the inactivation of glutathione peroxidase 4 (GPX4) and the up‐regulation of LPO levels, eventually realizing the synergistically enhanced ferroptosis. This facile and feasible design for versatile metal‐phenolic nanoformulations offers a new strategy for effectively improving ferroptosis efficiency and multimodal cancer therapies.

Advancements in nanomedicine delivery systems: unraveling immune regulation strategies for tumor immunotherapy.

This review highlights the significant role of nanodrug delivery systems (NDDS) in enhancing the efficacy of tumor immunotherapy. Focusing on the integration of NDDS with immune regulation strategies, it explores their transformative impacts on the tumor microenvironment and immune response dynamics. Key advancements include the optimization of drug delivery through NDDS, targeting mechanisms like immune checkpoint blockade and modulating the immunosuppressive tumor environment. Despite the progress, challenges such as limited clinical efficacy and complex manufacturing processes persist. The review emphasizes the need for further research to optimize these systems, potentially revolutionizing cancer treatment by improving delivery efficiency, reducing toxicity and overcoming immune resistance.

Identification of HOXC Gene Family as Prognostic and Immune-Related Biomarkers in Breast Cancer Through mRNA Transcriptional Profile and Experimental Validation.

Breast cancer (BC) is the most common malignancy in women worldwide, and more effective biomarkers are urgently needed for the prevention and treatment of BC. Our study aimed to investigate the role of the HOXC gene family (HOXCs) and its relationship with the immune response in BC. The differential expression of HOXCs and its clinical prognostic significance in BC were explored using bioinformatics analysis, and the cBioPortal database was used to evaluate the genetic mutation profile of the HOXCs in BC. The results indicated that the expression levels of HOXC4, 10, 11, 12, and 13 were significantly increased in BC tissues compared with the normal tissues, and expressions of these genes were closely associated with BC stage, among them, high expression levels of HOXC10 and HOXC13 predicted poor outcome in BC patients. In addition, to elucidate the essential role of HOXCs in the tumor microenvironment and immunotherapeutic response of BC, the impact of HOXCs on the regulation of immune infiltration in BC was comprehensively assessed. The result showed thatHOXC10 and HOXC13 expressions were significantly positively linked with the infiltration levels of CD8+T cell and M1 macrophage, while they werenegatively related to Mast and Natural killer cells, suggesting the important influence of HOXCs on regulating tumor immunity in BC patients. Lastly, the RT-qPCR assay was employed to validate HOXCs expression in samples of BC patients. In conclusion, HOXCs may be a promising prognostic indicator and couldregulate the immune infiltration in BC patients, thus being apromising targeted immunotherapy for BC.

Therapeutic liposomal combination to enhance chemotherapy response and immune activation of tumor microenvironment

Multiple oxaliplatin-resistance mechanisms have been proposed such as increase of anti-inflammatory M2 macrophages and lack of cytotoxic T-cells. Thereby oxaliplatin chemotherapy promotes an immunosuppressive tumor microenvironment and inhibits anti-tumor efficacy. It has been shown that toll-like receptor (TLR) agonists are capable of triggering broad inflammatory responses, which may potentially reduce oxaliplatin-resistance and improve the efficacy of chemotherapy. In this study, we established colorectal tumor-bearing zebrafish and mice, and investigated the effects of TLR agonists and oxaliplatin in macrophage function and anti-tumor T cell immunity as well as tumor growth control in vivo. To increase the potential of this strategy as well minimize side effects, neutral liposomes carrying oxaliplatin and cationic liposomes co-loaded with TLR agonists Poly I:C and R848 were employed for maximum immune activation. Both of two liposomal systems exhibited good physicochemical properties and excellent biological activities in vitro. The combination strategy delivered by liposomes showed more pronounced tumor regression and correlated with decreased M2 macrophage numbers in both zebrafish and mice. Increasing numbers of dendritic cells, DC maturation and T cell infiltration mediated via immunogenic cell death were observed in treated mice. Our study offers valuable insights into the potential of liposomal combination therapy to improve cancer treatment by reprogramming the tumor microenvironment and enhancing immune responses.

The Multifaceted Role of Neutrophils in NSCLC in the Era of Immune Checkpoint Inhibitors.

Lung cancer is the most common cause of cancer-related death in both males and females in the U.S. and non-small-cell lung cancer (NSCLC) accounts for 85%. Although the use of first- or second-line immune checkpoint inhibitors (ICIs) exhibits remarkable clinical benefits, resistance to ICIs develops over time and dampens the efficacy of ICIs in patients. Tumor-associated neutrophils (TANs) have an important role in modulating the tumor microenvironment (TME) and tumor immune response. The major challenge in the field is to characterize the TANs in NSCLC TME and understand the link between TAN-related immunosuppression with ICI treatment response. In this review, we summarize the current studies of neutrophil interaction with malignant cells, T-cells, and other components in the TME. Ongoing clinical trials are aimed at utilizing reagents that have putative effects on tumor-associated neutrophils, in combination with ICI. Elevated neutrophil populations and neutrophil-associated factors could be potential therapeutic targets to enhance anti-PD1 treatment in NSCLC.

The Current Landscape of Clinical Trials for Immunotherapy in Pancreatic Cancer: A State-of-the-Art Review.

Pancreatic cancer remains a lethal malignancy with a 5-year survival rate below 6% and about 500,000 deaths annually worldwide. Pancreatic adenocarcinoma, the most prevalent form, is commonly associated with diabetes, chronic pancreatitis, obesity, and smoking, mainly affecting individuals aged 60 to 80 years. This systematic review aims to evaluate the efficacy of immunotherapeutic approaches in the treatment of pancreatic cancer. A systematic search was conducted to identify clinical trials (Phases I-III) assessing immunotherapy in pancreatic cancer in PubMed/Medline, CINAHL, Scopus, and Web of Science, adhering to PRISMA Statement 2020 guidelines. The final search was completed on May 25, 2024. Ongoing trials were sourced from ClinicalTrials.gov and the World Health Organization's International Clinical Trials Registry Platform (ICTRP). Keywords such as "pancreatic," "immunotherapy," "cancer," and "clinical trial" were used across databases. Gray literature was excluded. Phase I trials, involving 337 patients, reported a median overall survival (OS) of 13.6 months (IQR: 5-62.5 months) and a median progression-free survival (PFS) of 5.1 months (IQR: 1.9-11.7 months). Phase II/III trials pooled in a total of 1463 participants had a median OS of 12.2 months (IQR: 2.5-35.55 months) and a median PFS of 8.8 months (IQR: 1.4-33.51 months). Immunotherapy shows potential for extending survival among pancreatic cancer patients, though results vary. The immunosuppressive nature of the tumor microenvironment and diverse patient responses underline the need for further research to optimize these therapeutic strategies.

The therapeutic and biomarker significance of ferroptosis in chronic myeloid leukemia.

The relationship between ferroptosis and the progression and treatment of hematological tumors has been extensively studied, although its precise association with chronic myeloid leukemia (CML) remains uncertain. Multi-transcriptome sequencing data were utilized to analyze the ferroptosis level of CML samples and its correlation with the tumor microenvironment, disease progression, and treatment response. Machine learning algorithms were employed to identify diagnostic ferroptosis-related genes (FRGs). The consensus clustering algorithm was applied to identify ferroptosis-related molecular subtypes. Clinical samples were collected for sequencing to validate the results obtained from bioinformatics analysis. Cell experiments were conducted to investigate the therapeutic efficacy of induced ferroptosis in drug-resistant CML. Ferroptosis scores were significantly lower in samples from patients with CML compared to normal samples, and these scores further decreased with disease progression and non-response to treatment. Most FRGs were downregulated in CML samples. A high ferroptosis score was also associated with greater immunosuppression and increased activity of metabolic pathways. Through support vector machine recursive feature elimination (SVM-RFE), least absolute shrinkage selection operator (LASSO), and random forest (RF) algorithms, we identified five FRGs (ACSL6, SLC11A2, HMOX1, SLC38A1, AKR1C3) that have high diagnostic value. The clinical diagnostic value of these five FRGs and their effectiveness in differentiating CML from other hematological malignancies were validated using additional validation cohorts and our real-world cohort. There are significant differences in immune landscape, chemosensitivity, and immunotherapy responsiveness between the two ferroptosis-related molecular subtypes. By conducting cellular experiments, we confirmed that CML-resistant cells are more sensitive to induction of ferroptosis and can enhance the sensitivity of imatinib treatment. Our study unveils the molecular signature of ferroptosis in samples from patients with CML. FRG identified by a variety of machine learning algorithms has reliable clinical diagnostic value. Furthermore, the characterization of different ferroptosis-related molecular subtypes provides valuable insights into individual patient characteristics and can guide clinical treatment strategies. Targeting and inducing ferroptosis holds great promise as a therapeutic approach for drug-resistant CML.

T cell proliferation-related subtypes, prognosis model and characterization of tumor microenvironment in head and neck squamous cell carcinoma

BackgroundThirty-three synthetic driver genes of T-cell proliferation have recently been identified through genome-scale screening. However, the tumor microenvironment (TME) cell infiltration, prognosis, and response to immunotherapy mediated by multiple T cell proliferation-related genes (TRGs) in patients with head and neck squamous cell carcinoma (HNSC) remain unclear. MethodsThis study examined the genetic and transcriptional changes in 771 patients with HNSC by analyzing the TRGs from two independent datasets. Two different subtypes were analyzed to investigate their relationship with immune infiltrating cells in the TME and patient prognosis. The study also developed and validated a risk score to predict overall survival (OS). Furthermore, to enhance the clinical utility of the risk score, an accurate nomogram was constructed by combining the characteristics of this study. ResultsThe low-risk score observed in this study was associated with high levels of immune checkpoint expression and TME immune activation, indicating a favorable OS outcome. Additionally, various factors related to risk scores were depicted. ConclusionThrough comprehensive analysis of TRGs in HNSC, our study has revealed the characteristics of the TME and prognosis, providing a basis for further investigation into TRGs and the development of more effective immunotherapy and targeted therapy strategies.

Stemness subtypes in lower-grade glioma with prognostic biomarkers, tumor microenvironment, and treatment response

Our research endeavors are directed towards unraveling the stem cell characteristics of lower-grade glioma patients, with the ultimate goal of formulating personalized treatment strategies. We computed enrichment stemness scores and performed consensus clustering to categorize phenotypes. Subsequently, we constructed a prognostic risk model using weighted gene correlation network analysis (WGCNA), random survival forest regression analysis as well as full subset regression analysis. To validate the expression differences of key genes, we employed experimental methods such as quantitative Polymerase Chain Reaction (qPCR) and assessed cell line proliferation, migration, and invasion. Three subtypes were assigned to patients diagnosed with LGG. Notably, Cluster 2 (C2), exhibiting the poorest survival outcomes, manifested characteristics indicative of the subtype characterized by immunosuppression. This was marked by elevated levels of M1 macrophages, activated mast cells, along with higher immune and stromal scores. Four hub genes—CDCA8, ORC1, DLGAP5, and SMC4—were identified and validated through cell experiments and qPCR. Subsequently, these validated genes were utilized to construct a stemness risk signature. Which revealed that Lower-Grade Glioma (LGG) patients with lower scores were more inclined to demonstrate favorable responses to immune therapy. Our study illuminates the stemness characteristics of gliomas, which lays the foundation for developing therapeutic approaches targeting CSCs and enhancing the efficacy of current immunotherapies. By identifying the stemness subtype and its correlation with prognosis and TME patterns in glioma patients, we aim to advance the development of personalized treatments, enhancing the ability to predict and improve overall patient prognosis.

The Role and Clinical Relevance of Glycolysis-Associated Genes on Immune Infiltration in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) poses a significant challenge with dismal survival rates, necessitating a deeper understanding of its molecular mechanisms and the development of improved therapies. Metabolic reprogramming, particularly heightened glycolysis, plays a crucial role in HCC progression. Glycolysis-associated genes (GAGs) emerge as key players in HCC pathogenesis, influencing the tumor microenvironment and immune responses. This study aims to investigate the intricate interplay between GAGs and the immune landscape within HCC, offering valuable insights into potential prognostic markers and therapeutic targets to enhance treatment strategies and patient outcomes. Through the exploration of GAGs, we have identified two distinct molecular glycolytic subtypes in HCC patients, each exhibiting significant differences in both the immune microenvironment and prognosis. A risk model comprising five key GAGs was formulated and subsequently evaluated for their predictive accuracy. Our findings underscore the diverse tumor microenvironment and immune responses associated with the varying glycolytic subtypes observed in HCC. The identified key GAGs hold promise as prognostic indicators for evaluating HCC risk levels, predicting patient outcomes, and guiding clinical treatment decisions, particularly in the context of anticipating responses to immunotherapy drugs.

Drug Repurposing and Molecular Insights in the Fight Against Breast Cancer

Breast Cancer (BC) is a complex disease with high incidence in developed countries. According to the World Health Organization (WHO), it is accounted for 11.7% of all new cancer cases worldwide in 2020, with an estimated 2.3 million new diagnosis every year. A 2.5% annual reduction in the disease mortality could prevent 2.5 million deaths worldwide between 2020 and 2040. In the current work systematic review was conducted for drugs under clinical trials or approved for treatment of BC. It was observed that many drugs were repurposed for BC treatment over the course of time even though they were originally developed for some other disease. This is called as Drug Repurposing. It is an approach that has gained significant attention in recent years as a promising alternative to traditional drug discovery, which is often costly, time-consuming, and has a high failure rate. Thirteen drugs were observed to be repurposed for BC treatment and we dig deep into their molecular background and reasons for their efficacies in BC treatment. Molecular targets of these drugs in the human system were predicted and protein interaction networks were analysed to work out the genes responsible for their repurposed events. Few genes seen in the disease progression, were BRCA1, BRCA2, PALB-2, ATM, TP53, PTEN, and HER2/neu participate in various biological pathways, such as the PI3K/Akt/mTOR and ER pathways, and biological processes such as the tumor microenvironment, epithelial-mesenchymal transition, and DNA damage response pathways. Mutations or alterations in these genes or pathways can lead to the development and progression, and understanding their roles that can help in the development of new diagnostic and therapeutic strategies. This study offers an in-silico perspective and a powerful tool to find potentially effective drugs by analysing the molecular mechanisms and signalling pathways involved in the disease progression.

Prediction of immunotherapy response of bladder cancer with a pyroptosis-related signature indicating tumor immune microenvironment.

Although prognostic models based on pyroptosis-related genes (PRGs) have been constructed in bladder cancer (BLCA), the comprehensive impact of these genes on tumor microenvironment (TME) and immunotherapeutic response has yet to be investigated. Based on expression profiles of 52 PRGs, we utilized the unsupervised clustering algorithm to identify PRGs subtypes and ssGSEA to quantify immune cells and hallmark pathways. Moreover, we screened feature genes of distinct PRGs subtypes and validated the associations with immune infiltrations in tissue using the multiplex immunofluorescence. Univariate, LASSO, and multivariate Cox regression analyses were employed to construct the scoring scheme. Four PRGs clusters were identified, samples in cluster C1 were infiltrated with more immune cells than those in others, implying a favorable response to immunotherapy. While the cluster C2, which shows an extremely low level of most immune cells, do not respond to immunotherapy. CXCL9/CXCL10 and SPINK1/DHSR2 were identified as feature genes of cluster C1 and C2, and the specimen with high CXCL9/CXCL10 was characterized by more CD8 + T cells, macrophages and less Tregs. Based on differentially expressed genes (DEGs) among PRGs subtypes, a predictive model (termed as PRGs score) including five genes (CACNA1D, PTK2B, APOL6, CDK6, ANXA2) was built. Survival probability of patients with low-PRGs score was significantly higher than those with high-PRGs score. Moreover, patients with low-PRGs score were more likely to benefit from anti-PD1/PD-L1 regimens. PRGs are closely associated with TME and oncogenic pathways. PRGs score is a promising indicator for predicting clinical outcome and immunotherapy response.

Unsupervised Analysis Reveals the Involvement of Key Immune Response Genes and the Matrisome in Resistance to BRAF and MEK Inhibitors in Melanoma.

Melanoma tumors exhibit a wide range of heterogeneity in genomics even with shared mutations in the MAPK pathway, including BRAF mutations. Consistently, adaptive drug resistance to BRAF inhibitors and/or BRAF plus MEK inhibitors also exhibits a wide range of heterogeneous responses, which poses an obstacle for discovering common genes and pathways that can be used in clinic for overcoming drug resistance. This study objectively analyzed two sets of previously published tumor genomics data comparing pre-treated melanoma tumors and BRAFi- and/or MEKi-resistant tumors. Heterogeneity in response to BRAFi and BRAFi/MEKi was evident because the pre-treated tumors and resistant tumors did not exhibit a tendency of clustering together. Differentially expressed gene (DEG) analysis revealed eight genes and two related enriched signature gene sets (matrisome and matrisome-associated signature gene sets) shared by both sets of data. The matrisome was closely related to the tumor microenvironment and immune response, and five out of the eight shared genes were also related to immune response. The PLXNC1 gene links the shared gene set and the enriched signature gene sets as it presented in all analysis results. As the PLXNC1 gene was up-regulated in the resistant tumors, we validated the up-regulation of this gene in a laboratory using vemurafenib-resistant cell lines. Given its role in promoting inflammation, this study suggests that resistant tumors exhibit an inflammatory tumor microenvironment. The involvement of the matrisome and the specific set of immune genes identified in this study may provide new opportunities for developing future therapeutic methods.

Circulating receptor activator of nuclear factor kappa-B ligand (RANKL) levels predict response to immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC)

BackgroundReceptor activator of nuclear factor kappa-B ligand (RANKL) can directly promote tumor growth and indirectly support tumor immune evasion by altering the tumor microenvironment and immune cell responses. This study...

Glutathione and acid dual-responsive bismuth-based nanosensitizer for chemo-mediated cancer sonodynamic therapy

Chemotherapeutic agents hold significant clinical potential in combating tumors. However, delivering these drugs to the tumor site for controlled release remains a crucial challenge. In this study, we synthesize and construct a glutathione (GSH) and acid dual-responsive bismuth-based nano-delivery platform (BOD), aiming for sonodynamic enhancement of docetaxel (DTX)-mediated tumor therapy. The bismuth nanomaterial can generate multiple reactive oxygen species under ultrasound stimulation. Furthermore, the loading of DTX to form BOD effectively reduces the toxicity of DTX in the bloodstream, ensuring its cytotoxic effect is predominantly exerted at the tumor site. DTX can be well released in high expression of GSH and acidic tumor microenvironment. Meanwhile, ultrasound can also promote the release of DTX. Results from both in vitro and in vivo experiments substantiate that the synergistic therapy involving chemotherapy and sonodynamic therapy significantly inhibits the growth and proliferation of tumor cells. This study provides a favorable paradigm for developing a synergistic tumor treatment platform for tumor microenvironment response and ultrasound-promoted drug release.

Establishment of a prognostic model for hypoxia-associated genes in OPSCC and revelation of intercellular crosstalk.

Hypoxia exerts a profound influence on the tumor microenvironment and immune response, shaping treatment outcomes and prognosis. Utilizing consistency clustering, we discerned two hypoxia subtypes in OPSCC bulk sequencing data from GEO. Key modules within OPSCC were identified through weighted gene correlation network analysis (WGCNA). Core modules underwent CIBERSORT immune infiltration analysis and GSEA functional enrichment. Univariate Cox and LASSO analyses were employed to construct prognostic models for seven hypoxia-related genes. Further investigation into clinical characteristics, the immune microenvironment, and TIDE algorithm prediction for immunotherapy response was conducted in high- and low-risk groups. scRNA-seq data were visually represented through TSNE clustering, employing the scissors algorithm to map hypoxia phenotypes. Interactions among cellular subpopulations were explored using the Cellchat package, with additional assessments of metabolic and transcriptional activities. Integration with clinical data unveiled a prevalence of HPV-positive patients in the low hypoxia and low-risk groups. Immunohistochemical validation demonstrated low TDO2 expression in HPV-positive (P16-positive) patients. Our prediction suggested that HPV16 E7 promotes HIF-1α inhibition, leading to reduced glycolytic activity, ultimately contributing to better prognosis and treatment sensitivity. The scissors algorithm effectively segregated epithelial cells and fibroblasts into distinct clusters based on hypoxia characteristics. Cellular communication analysis illuminated significant crosstalk among hypoxia-associated epithelial, fibroblast, and endothelial cells, potentially fostering tumor proliferation and metastasis.

NT157 as an Anticancer Drug Candidate That Targets Kinase- and Phosphatase-Mediated Signaling

Cancer, characterized by uncontrolled cell growth and metastasis, represents a significant challenge to public health. The IGF1/IGF1R axis plays a pivotal role in tumor proliferation and survival, presenting an attractive target for intervention. NT157, a small molecule tyrphostin, has emerged as a promising inhibitor of this axis, displaying potent antineoplastic effects across various cancer types. This review synthesizes the literature on NT157’s mechanism of action and its impact on cellular processes in experimental cancer models. Initially identified for inducing the serine phosphorylation of IRS1 and IRS2, leading to their degradation and inhibiting the IGF1R signaling cascade, subsequent studies revealed additional targets of NT157, including STAT3, STAT5, and AXL, suggesting a multifaceted mechanism. Experimental evidence demonstrates that NT157 effectively suppresses tumor growth, metastasis, and angiogenesis in diverse cancer models. Additionally, NT157 enhances chemotherapy efficacy in combination therapy. Moreover, NT157 impacts not only tumor cells but also the tumor microenvironment, modulating inflammation and immune responses by targeting cancer-associated fibroblasts, myeloid cells, and immune cells, creating a suppressive milieu hindering tumor progression and metastasis. In conclusion, NT157 exhibits remarkable versatility in targeting multiple oncogenic pathways and hallmarks of cancer, underscoring its potential as a promising therapeutic agent.

Synergistic antitumor immune response mediated by paclitaxel-conjugated nanohybrid oncolytic adenovirus with dendritic cell therapy.

Dendritic cell (DC)-based vaccines have emerged as a promising strategy in cancer immunotherapy due to low toxicity. However, the therapeutic efficacy of DC as a monotherapy is insufficient due to highly immunosuppressive tumor environment. To address these limitations of DC as immunotherapeutic agent, we have developed a polymeric nanocomplex incorporating (1) oncolytic adenovirus (oAd) co-expressing interleukin (IL)-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF) and (2) arginine-grafted bioreducible polymer with PEGylated paclitaxel (APP) to restore antitumor immune surveillance function in tumor milieu and potentiate immunostimulatory attributes of DC vaccine. Nanohybrid complex (oAd/APP) in combination with DC (oAd/APP+DC) induced superior expression level of antitumor cytokines (IL-12, GM-CSF, and interferon gamma) than either oAd/APP or DC monotherapy in tumor tissues, thus resulting in superior intratumoral infiltration of both endogenous and exogenous DCs. Furthermore, oAd/APP+DC treatment led superior migration of DC to secondary lymphoid organs, such as draining lymph nodes and spleen, in comparison with either monotherapy. Superior migration profile of DCs in oAd/APP+DC treatment group resulted in more prolific activation of tumor-specific T cells in these lymphoid organs and greater intratumoral infiltration of T cells. Additionally, oAd/APP+DC treatment led to lower subset of tumor infiltrating lymphocytes and splenocytes being immunosuppressive regulatory T cells than any other treatment groups. Collectively, oAd/APP+DC led to superior induction of antitumor immune response and amelioration of immunosuppressive tumor microenvironment to elicit potent tumor growth inhibition than either monotherapy.