M2 Macrophage Classification of Colorectal Cancer Reveals Intrinsic Connections with Metabolism Reprogramming and Clinical Characteristics.

Introduction: Immune cell interactions and metabolic changes are crucial in determining the tumor microenvironment and affecting various clinical outcomes. However, the clinical significance of metabolism evolution of immune cell evolution in colorectal cancer (CRC) remains unexplored. Methods: Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data were acquired from TCGA and GEO datasets. For the analysis of macrophage differentiation trajectories, we employed the R packages Seurat and Monocle. Consensus clustering was further applied to identify the molecular classification. Immunohistochemical results from AOM and AOM/DSS models were used to validate macrophage expression. Subsequently, GSEA, ESTIMATE scores, prognosis, clinical characteristics, mutational burden, immune cell infiltration, and the variance in gene expression among different clusters were compared. We constructed a prognostic model and nomograms based on metabolic gene signatures identified through the MEGENA framework. Results: We found two heterogeneous groups of M2 macrophages with various clinical outcomes through the evolutionary process. The prognosis of Cluster 2 was poorer. Further investigation showed that Cluster 2 constituted a metabolically active group while Cluster 1 was comparatively metabolically inert. Metabolic variations in M2 macrophages during tumor development are related to tumor prognosis. Additionally, Cluster 2 showed the most pronounced genomic instability and had highly elevated metabolic pathways, notably those associated with the ECM. We identified eight metabolic genes (PRELP, NOTCH3, CNOT6, ASRGL1, SRSF1, PSMD4, RPL31, and CNOT7) to build a predictive model validated in CRC datasets. Then, a nomogram based on the M2 risk score improved predictive performance. Furthermore, our study demonstrated that immune checkpoint inhibitor therapy may benefit patients with low-risk. Discussion: Our research reveals underlying relationships between metabolic phenotypes and immunological profiles and suggests a unique M2 classification technique for CRC. The identified gene signatures may be key factors linking immunity and tumor metabolism, warranting further investigations.

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.

[Porphyromonas gingivalis infection facilitates immune escape of esophageal cancer by enhancing YTHDF2-mediated Fas degradation].

OBJECTIVE: To investigate the effect of Porphyromonas gingivalis (Pg) infection on immune escape of oesophageal cancer cells and the role of YTHDF2 and Fas in this regulatory mechanism. METHODS: We examined YTHDF2 and Fas protein expressions in esophageal squamous cell carcinoma (ESCC) tissues with and without Pg infection using immunohistochemistry and in Pg-infected KYSE150 cells using Western blotting. The interaction between YTHDF2 and Fas was investigated by co-immunoprecipitation (Co-IP). Pg-infected KYSE150 cells with lentivirus-mediated YTHDF2 knockdown were examined for changes in expression levels of YTHDF2, cathepsin B (CTSB), Fas and FasL proteins, and the effect of E64 (a cathepsin inhibitor) on these proteins were observed. After Pg infection and E64 treatment, KYSE150 cells were co-cultured with human peripheral blood mononuclear cells (PBMCs), and the expressions of T cell-related effector molecules were detected by flow cytometry. RESULTS: ESCC tissues and cells with Pg infection showed significantly increased YTHDF2 expression and lowered Fas expression. The results of Co-IP demonstrated a direct interaction between YTHDF2 and Fas. In Pg-infected KYSE150 cells with YTHDF2 knockdown, the expression of CTSB was significantly reduced while Fas and FasL expressions were significantly increased. E64 treatment of KYSE150 cells significantly decreased the expression of CTSB without affecting YTHDF2 expression and obviously increased Fas and FasL expressions. Flow cytometry showed that in Pg-infected KYSE150 cells co-cultured with PBMCs, the expressions of Granzyme B and Ki67 were significantly decreased while PD-1 expression was significantly enhanced. CONCLUSION: Pg infection YTHDF2-dependently regulates the expression of Fas to facilitate immune escape of esophageal cancer and thus promoting cancer progression, suggesting the key role of YTHDF2 in regulating immune escape of esophageal cancer.

Development of a Humanized Antibody Targeting Extracellular HSP90α to Suppress Endothelial-Mesenchymal Transition-Enhanced Tumor Growth of Pancreatic Adenocarcinoma Cells.

Extracellular HSP90α (eHSP90α) is a promoter of tumor development and malignant progression. Patients with malignancies, including pancreatic ductal adenocarcinoma (PDAC), have generally shown 5~10-fold increases in serum/plasma eHSP90α levels. In this study, we developed a humanized antibody HH01 to target eHSP90α and evaluated its anticancer efficacy. HH01, with novel complementarity-determining regions, exhibits high binding affinity toward HSP90α. It recognizes HSP90α epitope sites 235AEEKEDKEEE244 and 251ESEDKPEIED260, with critical amino acid residues E237, E239, D240, K241, E253, and K255. HH01 effectively suppressed eHSP90α-induced invasive and spheroid-forming activities of colorectal cancer and PDAC cell lines by blocking eHSP90α's ligation with the cell-surface receptor CD91. In mouse models, HH01 potently inhibited the tumor growth of PDAC cell grafts/xenografts promoted by endothelial-mesenchymal transition-derived cancer-associated fibroblasts while also reducing serum eHSP90α levels, reflecting its anticancer efficacy. HH01 also modulated tumor immunity by reducing M2 macrophages and reinvigorating immune T-cells. Additionally, HH01 showed low aggregation propensity, high water solubility, and a half-life time of >18 days in mouse blood. It was not cytotoxic to retinal pigmented epithelial cells and showed no obvious toxicity in mouse organs. Our data suggest that targeting eHSP90α with HH01 antibody can be a promising novel strategy for PDAC therapy.

Modulating Tumor Immunity by Targeting Tumor Fibrotic Stroma and Angiogenic Vessels for Lung Cancer Treatment.

Fibrotic stroma and angiogenic tumor vessels play an important role in modulating tumor immunity. We previously reported a rationally designed protein (ProAgio) that targets integrin αvß3 at a novel site. ProAgio induces the apoptosis of cells that express high levels of the integrin. Both activated cancer-associated fibroblasts (CAFs) and angiogenic endothelial cells (aECs) in tumors express high levels of integrin αvß3. ProAgio simultaneously and specifically induces apoptosis in CAFs and aECs in tumors. We provide evidence here that the depletion of CAFs and the elimination of leaky tumor angiogenic vessels by ProAgio alter tumor immunity. ProAgio reduces CD4+ Treg and Myeloid-derived suppressor cells (MDSCs), increases CD8+ T-cells, and increases the M1/M2 macrophage ratio in the tumor. The depletion of dense fibrotic stroma (CAFs) by ProAgio decreases the Programmed Death Ligand 1 (PDL-1) levels in the stroma areas surrounding the tumors, and thus strongly increases the delivery of anti-PDL-1 antibody to the target cancer cells. The impact of ProAgio on tumor immunity provides strong synergistical effects of checkpoint inhibitors on lung cancer treatment.

Lrp10 suppresses IL7R limiting CD8 T cell homeostatic expansion and anti-tumor immunity.

Signals emanating from the T-cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 T-cell fate. Understanding how these signals respond to homeostatic and microenvironmental cues can reveal new ways to therapeutically direct T-cell function. Through forward genetic screening in mice, we discover that loss-of-function mutations in LDL receptor-related protein 10 (Lrp10) cause naive and central memory CD8 T cells to accumulate in peripheral lymphoid organs. Lrp10 encodes a conserved cell surface protein of unknown immunological function. T-cell activation induces Lrp10 expression, which post-translationally suppresses IL7 receptor (IL7R) levels. Accordingly, Lrp10 deletion enhances T-cell homeostatic expansion through IL7R signaling. Lrp10-deficient mice are also intrinsically resistant to syngeneic tumors. This phenotype depends on dense tumor infiltration of CD8 T cells, which display increased memory cell characteristics, reduced terminal exhaustion, and augmented responses to immune checkpoint inhibition. Here, we present Lrp10 as a new negative regulator of CD8 T-cell homeostasis and a host factor that controls tumor resistance with implications for immunotherapy.

Impact of high-salt diet in health and diseases and its role in pursuit of cancer immunotherapy by modulating gut microbiome.

Cancer chemotherapy remains an area of concern, as many of the therapies are uncomfortable involving side effects and unpleasant experiences. These factors could further reduce patient's quality of life, and even endanger their life. Many therapeutic strategies have been tried to reduce the unpleasant side effects and increase the treatment effectiveness; however, none have shown to have promising effects. One of the main hindrances to cancer therapy is the escape strategies by tumor cells to the immune attack. Promoting inflammation in the tumor microenvironment is the cornerstone and key therapeutic target in cancer chemotherapy. High-salt diet (HSD) intake, though it has deleterious effects on human health by promoting chronic inflammation, is found to be advantageous in the tumor microenvironment. Studies identified HSD favors an increased abundance of Bifidobacterium species in the tumor environment due to gut barrier alteration, which, in turn, promotes inflammation and favors improved response to cancer chemotherapy. A review of the literature was carried out to find out the effects of an HSD on health and diseases, with special mention of its effect on cancer chemotherapy. Studies emphasized HSD would block the myeloid-derived suppressor cells which will enhance the tumor immunity. Exploration of the precise mechanism of simple HSD regime/ingestion of specific bacterial species as probiotics will be effective and essential to formulate the game-changing cancer chemotherapy. With the modern era of healthcare moving toward precision medicine where the physician can choose the treatment option suitable for the individual, HSD regime/ingestion of specific bacterial species can be considered.

Hainanenin-1, an oncolytic peptide, triggers immunogenic cell death via STING activation in triple-negative breast cancer.

BACKGROUND: In triple-negative breast cancer (TNBC) therapy, insufficient tumor infiltration by lymphocytes significantly hinders the efficacy of immune checkpoint inhibitors. We have previously demonstrated that Hainanenin-1 (HN-1), a host defense peptide (HDP) identified from Hainan frog skin, induces breast cancer apoptosis and boots anti-tumor immunity via unknown mechanism. METHODS: We used in vitro experiments to observe immunogenic cell death (ICD) indicators in HN-1-treated TNBC cell lines, a mouse tumor model to verify HN-1 promotion of mice anti-tumor immune response, and an in vitro drug sensitivity test of patient-derived breast cancer cells to verify the inhibitory effect of HN-1. RESULTS: HN-1 induced ICD in TNBC in a process during which damage-associated molecular patterns (DAMPs) were released that could further increase the anti-tumor immune response. The secretion level of interleukin 2 (IL-2), IL-12, and interferon γ in the co-culture supernatant was increased, and dendritic cells (DCs) were activated via a co-culture with HN-1-pretreated TNBC cells. As a result, HN-1 increased the infiltration of anti-tumor immune cells (DCs and T lymphocytes) in the mouse model bearing both 4T1 and EMT6 tumors. Meanwhile, regulatory T cells and myeloid-derived suppressor cells were suppressed. In addition, HN-1 induced DNA damage, and double-strand DNA release in the cytosol was significantly enhanced, indicating that HN-1 might stimulate ICD via activation of STING pathway. The knockdown of STING inhibited HN-1-induced ICD. Of note, HN-1 exhibited inhibitory effects on patient-derived breast cancer cells under three-dimensional culture conditions. CONCLUSIONS: Collectively, our study demonstrated that HN-1 could be utilized as a potential compound that might augment immunotherapy effects in patients with TNBC.

Metformin as a therapeutic agent for obesity-associated immune dysfunction.

Obesity is associated with impaired immune function, characterized by inflammation, and leading to poor response to infection, impaired vaccine response, increased susceptibility to autoimmune disease, and increased risk of cancer and cancer mortality. Worse, there is evidence that weight loss alone may be insufficient to reverse the immune dysfunction caused by obesity. It is therefore critically important to identify alternative therapeutic approaches to decrease the negative effects of obesity-associated inflammation. Here, we will review evidence that the antidiabetic drug metformin may be considered as a therapeutic agent for obesity-associated immune dysfunction. Metformin has immune-modulatory effects, stimulating or suppressing the immune response in both a cell-specific and disease-specific manner. Although the mechanism of action of metformin on the immune system remains to be fully elucidated, there is strong evidence that metformin enters select immune cells and disrupts electron transport, leading to both AMPK-dependent and AMPK-independent effects on immune cell differentiation and cytokine production. These effects of metformin on immune cells have been shown to improve immune responses to infection, autoimmunity, and cancer.

Elucidating CTLA-4's role in tumor immunity: a comprehensive overview of targeted antibody therapies and clinical developments.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) emerges as a key single-chain transmembrane glycoprotein predominantly expressed in effector T cells and regulatory T cells. It plays a crucial role in tumor immunity by modulating T cell responses. Specifically, CTLA-4 dampens T cell activation and proliferation while bolstering the survival of regulatory T cell through its competitive interaction with B7 family molecules, thereby aiding tumor cells in eluding immune detection. Given CTLA-4's significant influence on tumor immune dynamics, an array of anti-CTLA-4 antibody therapeutics have been clinically developed to combat various malignancies, including melanoma, renal cell carcinoma, colorectal carcinoma, hepatocellular carcinoma, non-small cell lung carcinoma, and pleural mesothelioma, demonstrating notable clinical therapeutic effects. This paper aims to delve into CTLA-4's integral role in tumor immunity and to encapsulate the latest advancements in the clinical research of anti-CTLA-4 antibody.

Combination of microparticles vaccine with MSI-1436 exerts a strong immune response for hepatocellular carcinoma.

Although tumor cell-derived microparticles (MPs) vaccines have reportedly induced anti-tumor immune reactions for various cancers, the mechanism by which MPs derived from Hepa1-6 cells are taken up by dendritic cells (DCs) and provide the MPs antigens message to CD8+ T cells to exert their anti-hepatocellular carcinoma (HCC) effects remain unclear. Furthermore, the role of MPs in combination with the small-molecule drug MSI-1436, an inhibitor of protein tyrosine phosphatase 1B (PTP1B), in HCC has not yet been reported. In this study, protein mass spectrometry combined with cytology revealed that MPs are mainly taken up by DCs via the clathrin-mediated endocytosis and phagocytosis pathway and localized mainly in lysosomes. High concentration of tumor necrosis factor (TNF)-α and interferon (IFN)-γ were detected in CD8+ T cells stimulated with MPs-loaded DCs. Moreover, MPs combined with MSI-1436 further suppressed the proliferation of HCC cells in C57BL/6 tumor-bearing mice, which was closely correlated with CD4+/CD8+ T cells counts in peripheral blood, spleen, and the tumor microenvironment. Mechanistically, the combination of MPs and MSI-1436 exerts a more powerful anti-HCC effect, which may be related to the further inhibition of the expression of PTP1B. Overall, MPs combined with MSI-1436 exerted stronger anti-tumor effects than MPs or MSI-1436 alone. Therefore, the combination of MPs and MSI-1436 may be a promising means of treating HCC.

The multifaceted role of PCSK9 in cancer pathogenesis, tumor immunity, and immunotherapy.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), a well-known regulator of cholesterol metabolism and cardiovascular diseases, has recently garnered attention for its emerging involvement in cancer biology. The multifunctional nature of PCSK9 extends beyond lipid regulation and encompasses a wide range of cellular processes that can influence cancer progression. Studies have revealed that PCSK9 can modulate signaling pathways, such as PI3K/Akt, MAPK, and Wnt/ß-catenin, thereby influencing cellular proliferation, survival, and angiogenesis. Additionally, the interplay between PCSK9 and cholesterol homeostasis may impact membrane dynamics and cellular migration, further influencing tumor aggressiveness. The central role of the immune system in monitoring and controlling cancer is increasingly recognized. Recent research has demonstrated the ability of PCSK9 to modulate immune responses through interactions with immune cells and components of the tumor microenvironment. This includes effects on dendritic cell maturation, T cell activation, and cytokine production, suggesting a role in shaping antitumor immune responses. Moreover, the potential influence of PCSK9 on immune checkpoints such as PD1/PD-L1 lends an additional layer of complexity to its immunomodulatory functions. The growing interest in cancer immunotherapy has prompted exploration into the potential of targeting PCSK9 for therapeutic benefits. Preclinical studies have demonstrated synergistic effects between PCSK9 inhibitors and established immunotherapies, offering a novel avenue for combination treatments. The strategic manipulation of PCSK9 to enhance tumor immunity and improve therapeutic outcomes presents an exciting area for further investigations. Understanding the mechanisms by which PCSK9 influences cancer biology and immunity holds promise for the development of novel immunotherapeutic approaches. This review aims to provide a comprehensive analysis of the intricate connections between PCSK9, cancer pathogenesis, tumor immunity, and the potential implications for immunotherapeutic interventions.

Establishment of a prognostic model for pancreatic cancer based on vesicle-mediated transport protein-related genes.

This study attempted to build a prognostic riskscore model for pancreatic cancer (PC) patients based on vesicle-mediated transport protein-related genes (VMTGs). We initially conducted differential expression analysis and Cox regression analysis, followed by the construction of a riskscore model to classify PC patients into high-risk (HR) and low-risk (LR) groups. The GEO GSE62452 dataset further validated the model. Kaplan-Meier survival analysis was employed to analyze the survival rate of the HR group and LR group. Cox analysis confirmed the independent prognostic ability of the riskscore model. Additionally, we evaluated immune status in both HR and LR groups, utilizing data from the GDSC database to predict drug response among PC patients. We identified six PC-specific genes from 724 VMTGs. Survival analysis revealed that the survival rate of the HR group was lower than that of the LR group (P<0.05). Cox analysis confirmed that the prognostic riskscore model could independently predict the survival status of PC patients (P<0.001). Immunological analysis revealed that the ESTIMATE score, immune score, and stroma score of the HR group were considerably lower than those of the LR group, and the tumor purity score of the HR group was higher. The IC50 values of Gemcitabine, Irinotecan, Oxaliplatin, and Paclitaxel in the LR group were considerably lower than those in the HR group (P<0.001). In summary, the VMTG-based prognostic riskscore model could stratify PC risk and effectively predict the survival of PC patients.

Boron Neutron Capture Therapy-Derived Extracellular Vesicles via DNA Accumulation Boost Antitumor Dendritic Cell Vaccine Efficacy.

Radiated tumor cell-derived extracellular vesicles (RT-EVs) encapsulate abundant DNA fragments from irradiated tumor cells, in addition to acting as integrators of multiple tumor antigens. Accumulating evidence indicates these DNA fragments from damaged cells are involved in downstream immune responses, but most of them are degraded in cells before incorporation into derived RT-EVs, thus the low abundance of DNA fragments limits immune responses of RT-EVs. Here, this study found that different radiations affected fates of DNA fragments in RT-EVs. Boron neutron capture therapy (BNCT) induced DNA accumulation in RT-EVs (BEVs) by causing more DNA breaks and DNA oxidation resisting nuclease degradation. This is attributed to the high-linear energy transfer (LET) properties of alpha particles from the neutron capture reaction of 10B. When being internalized by dendritic cells (DCs), BEVs activated the DNA sensing pathway, resulting in functional enhancements including antigen presentation, migration capacity, and cytokine secretion. After vaccination of the BEVs-educated DCs (BEV@BMDCs), the effector T cells significantly expanded and infiltrated into tumors, suggesting robust anti-tumor immune activation. BEV@BMDCs not only effectively inhibited the primary tumor growth and metastasis formation but also elicited long-term immune memory. In conclusion, a successful DC vaccine is provided as a promising candidate for tumor vaccine.

Transition Metal Oxide Nanomaterials: New Weapons to Boost Anti-Tumor Immunity Cycle.

Semiconductor nanomaterials have emerged as a significant factor in the advancement of tumor immunotherapy. This review discusses the potential of transition metal oxide (TMO) nanomaterials in the realm of anti-tumor immune modulation. These binary inorganic semiconductor compounds possess high electron mobility, extended ductility, and strong stability. Apart from being primary thermistor materials, they also serve as potent agents in enhancing the anti-tumor immunity cycle. The diverse metal oxidation states of TMOs result in a range of electronic properties, from metallicity to wide-bandgap insulating behavior. Notably, titanium oxide, manganese oxide, iron oxide, zinc oxide, and copper oxide have garnered interest due to their presence in tumor tissues and potential therapeutic implications. These nanoparticles (NPs) kickstart the tumor immunity cycle by inducing immunogenic cell death (ICD), prompting the release of ICD and tumor-associated antigens (TAAs) and working in conjunction with various therapies to trigger dendritic cell (DC) maturation, T cell response, and infiltration. Furthermore, they can alter the tumor microenvironment (TME) by reprogramming immunosuppressive tumor-associated macrophages into an inflammatory state, thereby impeding tumor growth. This review aims to bring attention to the research community regarding the diversity and significance of TMOs in the tumor immunity cycle, while also underscoring the potential and challenges associated with using TMOs in tumor immunotherapy.

Glucocorticoids in lung cancer: Navigating the balance between immunosuppression and therapeutic efficacy.

Glucocorticoids (GCs), a class of hormones secreted by the adrenal glands, are released into the bloodstream to maintain homeostasis and modulate responses to various stressors. These hormones function by binding to the widely expressed GC receptor (GR), thereby regulating a wide range of pathophysiological processes, especially in metabolism and immunity. The role of GCs in the tumor immune microenvironment (TIME) of lung cancer (LC) has been a focal point of research. As immunosuppressive agents, GCs exert a crucial impact on the occurrence, progression, and treatment of LC. In the TIME of LC, GCs act as a constantly swinging pendulum, simultaneously offering tumor-suppressive properties while diminishing the efficacy of immune-based therapies. The present study reviews the role and mechanisms of GCs in the TIME of LC.

The correlation between TRIM28 expression and immune checkpoints in CRPC.

This study delves into the unexplored realm of castration-resistant prostate cancer (CRPC) by investigating the role of TRIM28 and its intricate molecular mechanisms using high-throughput single-cell transcriptome sequencing and advanced bioinformatics analysis. Our comprehensive examination unveiled dynamic TRIM28 expression changes, particularly in immune cells such as macrophages and CD8+ T cells within CRPC. Correlation analyses with TCGA data highlighted the connection between TRIM28 and immune checkpoint expression and emphasized its pivotal influence on the quantity and functionality of immune cells. Using TRIM28 knockout mouse models, we identified differentially expressed genes and enriched pathways, unraveling the potential regulatory involvement of TRIM28 in the cGAS-STING pathway. In vitro, experiments further illuminated that TRIM28 knockout in prostate cancer cells induced a notable anti-tumor immune effect by inhibiting M2 macrophage polarization and enhancing CD8+ T cell activity. This impactful discovery was validated in an in situ transplant tumor model, where TRIM28 knockout exhibited a deceleration in tumor growth, reduced proportions of M2 macrophages, and enhanced infiltration of CD8+ T cells. In summary, this study elucidates the hitherto unknown anti-tumor immune role of TRIM28 in CRPC and unravels its potential regulatory mechanism via the cGAS-STING signaling pathway. These findings provide novel insights into the immune landscape of CRPC, offering promising directions for developing innovative therapeutic strategies.

Pan-cancer analysis of disulfidptosis with potential implications in prognosis, immune microenvironment, and drug resistance in human cancer.

To get a systematic assessment of disulfidptosis-related genes across human cancers and explore the predictive role of disulfidptosis in cancer drug sensitivity. We developed a score-level model to quantify the level of disulfidptosis in 33 human cancers using TCGA data. The mRNA expression and protein levels of disulfidptosis-related genes in human cancer cells and tissues were detected and retrieved from the Human Protein Atlas. Multiomics bioinformatic analyses were performed to evaluate disulfidptosis-related gene characteristics as well as the effect of disulfidptosis on the cancer immune microenvironment and drug resistance. Thirty cancers showed significantly different expression levels of disulfidptosis-related genes between normal and tumor samples. The mRNA expression and protein level of disulfidptosis-related genes were consistent with TCGA databases in lung cancer and hepatocellular carcinoma. We also found that altered levels of the disulfidptosis score expression were usually related to patient prognosis, and high expression of disulfidptosis-related genes was associated with drug resistance in different cancer types. Our study illustrates the characterization of disulfidptosis in multiple cancer types and highlights its potential value as a predictive biomarker of drug response, which can pave the way for further investigation of the prognostic and therapeutic potential of disulfidptosis.

CLEC7A regulates M2 macrophages to suppress the immune microenvironment and implies poorer prognosis of glioma.

Background: Gliomas constitute a category of malignant tumors originating from brain tissue, representing the majority of intracranial malignancies. Previous research has demonstrated the pivotal role of CLEC7A in the progression of various cancers, yet its specific implications within gliomas remain elusive. The primary objective of this study was to investigate the prognostic significance and immune therapeutic potential of CLEC7A in gliomas through the integration of bioinformatics and clinical pathological analyses. Methods: This investigation involved examining and validating the relationship between CLEC7A and glioma using samples from Hospital, along with data from TCGA, GEO, GTEx, and CGGA datasets. Subsequently, we explored its prognostic value, biological functions, expression location, and impact on immune cells within gliomas. Finally, we investigated its potential impact on the chemotaxis and polarization of macrophages. Results: The expression of CLEC7A is upregulated in gliomas, and its levels escalate with the malignancy of tumors, establishing it as an independent prognostic factor. Functional enrichment analysis revealed a significant correlation between CLEC7A and immune function. Subsequent examination of immune cell differential expression demonstrated a robust association between CLEC7A and M2 macrophages. This conclusion was further substantiated through single-cell analysis, immunofluorescence, and correlation studies. Finally, the knockout of CLEC7A in M2 macrophages resulted in a noteworthy reduction in macrophage chemotaxis and polarization factors. Conclusion: CLEC7A expression is intricately linked to the pathology and molecular characteristics of gliomas, establishing its role as an independent prognostic factor for gliomas and influencing macrophage function. It could be a promising target for immunotherapy in gliomas.

Injectable hybrid hydrogels enable enhanced combination chemotherapy and roused anti-tumor immunity in the synergistic treatment of pancreatic ductal adenocarcinoma.

Chemotherapy and immunotherapy have shown no significant outcome for unresectable pancreatic ductal adenocarcinoma (PDAC). Multi-drug combination therapy has become a consensus in clinical trials to explore how to arouse anti-tumor immunity and meanwhile overcome the poorly tumoricidal effect and the stroma barrier that greatly hinders drug penetration. To address this challenge, a comprehensive strategy is proposed to fully utilize both the ferroptotic vulnerability of PDAC to potently irritate anti-tumor immunity and the desmoplasia-associated focal adhesion kinase (FAK) to wholly improve the immunosuppressive microenvironment via sustained release of drugs in an injectable hydrogel for increasing drug penetration in tumor location and averting systematic toxicity. The injectable hydrogel ED-M@CS/MC is hybridized with micelles loaded with erastin that exclusively induces ferroptosis and a FAK inhibitor defactinib for inhibiting stroma formation, and achieves sustained release of the drugs for up to 12 days. With only a single intratumoral injection, the combination treatment with erastin and defactinib produces further anti-tumor performance both in xenograft and KrasG12D-engineered primary PDAC mice and synergistically promotes the infiltration of CD8+ cytotoxic T cells and the reduction of type II macrophages. The findings may provide a novel promising strategy for the clinical treatment of PDAC.