Checkpoint Inhibitors Research Articles

Long-term cardiovascular outcomes of immune checkpoint inhibitor-related myocarditis: A large single-centre analysis.

Immune checkpoint inhibitors (ICI) are the cornerstone of modern oncology; however, side effects such as ICI-related myocarditis (irM) can be fatal. Recently, Bonaca proposed criteria for irM; however, it is unknown if they correlate well with cardiovascular (CV) ICI-related adverse events. Additionally, whether incident irM portends worse long-term CV outcomes remains unclear. We aimed to determine the incidence of long-term CV comorbidities and CV mortality among irM patients. The ICI-related adverse event (irAE) registry was queried to identify irM patients by using Bonaca criteria. Random controls were selected after excluding patients with other concomitant irAEs. Patients' demographics, comorbidities and myocarditis presenting features were gathered. Outcomes included 2-year freedom from CV comorbidities (composite of atrial fibrillation, stroke, myocardial infarction and heart failure) and freedom from CV death. IrM was treated as a time-varying covariate. Seventy-six patients developed irM at a median of 167days (mean age 69, 63.2% male, 47% lung cancer). Majority of patients had new wall motion abnormalities or EKG changes on presentation. Mean LVEF was 43%, median peak TnT was 0.81, and median NTproBNP was 2057 at irM onset. Two-year freedom from CV comorbidities (67% vs 86.8%, P<0.001) and death (93.4% vs 99.3%, P=0.003) was lower among irM patients. Incident irM was an independent predictor of CV death (HR 8.28, P=0.048), but not CV comorbidities (HR 2.21, P=0.080). This is the largest case-control study on irM highlighting worse long-term CV outcomes. Future studies are needed to establish appropriate therapeutic strategies and efficient screening strategies for irM survivors.

Interleukins: Role in cancer and its immunotherapy

Interleukins are a very important family of cytokines; they are the messengers that assist immune cells to communicate with each other. Interleukins plays a pivotal role in innate and adaptive immune responses by balancing immune cell proliferation, differentiation and regulation. Interleukins aid immune cells in killing cancer cells while simultaneously assisting cancer cells in evading the immune response which leads tumor formation. Some interleukins are very effective at activating effector immune cells to kill cancer cells and also used for cancer immunotherapy. Interleukins are utilized in cancer immunotherapy alone or in combination with other therapies such as CAR-T, checkpoint inhibitors, or chemotherapy. In this review, we will explore the role of different interleukins in cancer and how researchers modified and therapeutically used them to treat cancer (e.g. IL-2, IL-12, IL-15, IL-17, IL-6, IL-18 etc.,).

Nuclear imaging of PD-L1 expression promotes the synergistic antitumor efficacy of targeted radionuclide therapy and immune checkpoint blockade.

In order to maximize synergistic effect of targeted radionuclide therapy (TRT) and immune checkpoint blockade (ICB) as well as reduce the toxicity, we pioneered a strategy guided by PD-L1-targeted nuclear medicine imaging for the combination of TRT and ICB towards precision cancer therapy. As a novel targeted radiotherapeutic agent, 177Lu-AB-3PRGD2 targeting integrin αvβ3 was developed to achieve sustained antitumor effect by introducing an albumin binder (AB) into the structure of 3PRGD2. The 177Lu-AB-3PRGD2 TRT as well as different types of combination therapies of 177Lu-AB-3PRGD2 TRT and anti-PD-L1 ICB were performed in animal models. The changes of PD-L1 expression in tumors after TRT were evaluated in vitro and in vivo by PD-L1-specific SPECT/CT imaging of 99mTc-MY1523. 177Lu-AB-3PRGD2 showed improved tumor uptake and prolonged tumor retention, leading to significantly enhanced tumor growth suppression. Moreover, 177Lu-AB-3PRGD2 TRT remodeled the tumor immune microenvironment by upregulating PD-L1 expression and increasing tumor-infiltrating CD8+ T cells, facilitating immunotherapy. We found that the anti-PD-L1 treatment was more effective during the upregulation of tumor PD-L1 expression, and the time window could be determined by 99mTc-MY1523 SPECT/CT. We developed a novel and long-acting radiotherapeutic agent 177Lu-AB-3PRGD2, and pioneered a strategy guided by PD-L1-targeted nuclear medicine imaging for the combination of TRT and ICB towards precision cancer therapy, optimizing the therapeutic efficacy and reducing the cost and potential toxicity risks. This strategy could also be adapted for clinical practice, combining conventional radiotherapy or chemotherapy with ICB to enhance therapeutic efficacy.

HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells

Hypoxia is a common feature in various pathophysiological contexts, including tumor microenvironment, and IFN-γ is instrumental for anti-tumor immunity. HIF1α has long been known as a primary regulator of cellular adaptive responses to hypoxia, but its role in IFN-γ induction in hypoxic T cells is unknown. Here, we show that the HIF1α-glycolysis axis controls IFN-γ induction in both human and mouse T cells, activated under hypoxia. Specific deletion of HIF1α in T cells (Hif1α–/–) and glycolytic inhibition suppresses IFN-γ induction. Conversely, HIF1α stabilization by hypoxia and VHL deletion in T cells (Vhl–/–) increases IFN-γ production. Hypoxic Hif1α–/– T cells are less able to kill tumor cells in vitro, and tumor-bearing Hif1α–/– mice are not responsive to immune checkpoint blockade (ICB) therapy in vivo. Mechanistically, loss of HIF1α greatly diminishes glycolytic activity in hypoxic T cells, resulting in depleted intracellular acetyl-CoA and attenuated activation-induced cell death (AICD). Restoration of intracellular acetyl-CoA by acetate supplementation re-engages AICD, rescuing IFN-γ production in hypoxic Hif1α–/– T cells and re-sensitizing Hif1α–/– tumor-bearing mice to ICB. In summary, we identify HIF1α-regulated glycolysis as a key metabolic control of IFN-γ production in hypoxic T cells and ICB response.

Immunotherapy-induced reprogramming of cancer-associated fibroblasts can promote tumor progression.

Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic; however, ICI initiation can also cause an unexpectedly rapid acceleration of cancer progression in some patients. Here, we used a murine syngeneic melanoma model to conduct mechanistic analysis of cancer-associated fibroblast (CAF) function in cancer progression in the context of immunotherapy. We found that after ICI treatment CAFs acquire inflammatory properties, which can promote tumor progression. Mechanistically, we show that T-cell-derived interferon-γ (IFN-γ) stimulates production of tumor necrosis factor-α (TNF-α) by macrophages, facilitating CAF conversion to inflammatory CAFs. Our findings suggest that CAF/immune cell crosstalk plays an essential role in ICI-associated tumor progression.

The Effect of PD-1/PD-L1 Inhibitor and Statin Combination Therapy on Overall Survival and Gastrointestinal Toxicity.

Immune checkpoint inhibitors (ICIs), such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors, have been approved to treat a variety of cancers. Recently, studies have suggested that ICIs and statins are synergistic. However, the addition of statins to ICI therapy may increase the risk of gastrointestinal immune-related adverse events (irAEs). We investigated the effect of combination therapy with PD-1 and/or L1 inhibitors and statins on overall survival and gastrointestinal irAEs. We reviewed the charts of patients with select cancers who received PD-1 and/or PD-L1 inhibitors and statins. The incidence of gastrointestinal irAEs and overall survival were compared with that in a matched control group of patients who received PD-1 and/or PD-L1 inhibitors without statins. Of the 823 patients in the statin group, 707 received PD-1 inhibitors, 86 received PD-L1 inhibitors, and 30 received both. Patients taking any statins (10.8%) and those taking high-intensity statins (15.8%) had higher rates of gastrointestinal irAEs than patients not taking statins (8.7%; P=0.046 and 0.006, respectively). Compared with the nonstatin treatments, statin use was associated with improved overall survival for patients taking PD-1 inhibitors (P<0.001) and for patients with (P=0.021) and without (P<0.001) gastrointestinal irAEs. Synergism of statins with PD-1 and PD-L1 inhibitors continues to be a developing field of interest. Our data demonstrate the survival benefit of combination therapy with PD-1 and/or PD-L1 inhibitors and statins, warranting further investigation.

Immune-related adverse events in small-cell lung cancer patients treated with immune checkpoint inhibitors: a comprehensive analysis from the FDA adverse event reporting system

BackgroundThe discovery and development of immune checkpoint inhibitors (ICIs) have resulted in their application as a novel therapeutic strategy for patients with small-cell lung cancer (SCLC). However, a comprehensive analysis of the potential adverse effects of ICIs in patients with SCLC remains to be conducted.MethodsAdverse event (ADE) reports relating to SCLC patients, submitted to the FDA Adverse Event Reporting System (FAERS) from the first quarter of 2013 to the second quarter of 2022, were extracted for analysis. The extracted data were subsequently screened and analyzed using the reporting odds ratio (ROR) method to assess the AE reports.ResultsA total of 4,522 ADE reports were obtained from patients with SCLC who had received either chemotherapy alone or a combination of ICIs with chemotherapy. The ROR analysis identified a total of 91 immune-related adverse events in SCLC patients associated with the ICIs (SCLC-irAEs).ConclusionThis study revealed that the adverse effects resulting from irAEs in SCLC patients predominantly affected the hematologic and gastrointestinal systems, with the most severe cases potentially leading to fatality.

Tumor-Derived Extracellular Vesicles Enable Tumor Tropism Chemo-Genetherapy for Local Immune Activation in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is highly heterogeneous, lacks accessible therapeutic targets, and features an immunosuppressive tumor microenvironment (TME). Anthracycline-based chemotherapy remains the primary treatment method for TNBC, while the current popular immune checkpoint inhibitors persistently encounter therapeutic resistance. Therefore, there is an urgent need to explore combined therapeutic strategies to remodel the TME and improve the treatment response. Considering the highly specific homing ability of tumor cell-derived vesicles and the key role of the signal transduction and activation of the transcription factor 3 (STAT3) pathway in TNBC, we propose a synergistic therapeutic strategy that integrates gene therapy, chemotherapy, and immunotherapy based on STAT3 short interfering RNA (siSTAT3) and doxorubicin (DOX)-functionalized tumor-derived extracellular vesicles (TEVs) (siSTAT3-DOX@TEV). The in vitro and in vivo results demonstrate that siSTAT3-DOX@TEV target tumor tissues precisely, downregulate STAT3 expression, and synergistically and efficiently induce immunogenic death, thereby reversing the immunosuppressive TME. Moreover, mass cytometry and immunohistochemistry reveal the local immune activation effect of siSTAT3-DOX@TEV, with a significant increase in M1 macrophages, CD4+ T cells, and CD8+ T cells in tumor tissues. These results provide strong hints for the development of TEV-based chemo-gene therapeutic agents for TNBC treatment at the clinical level.

Unraveling the Impact of Sarcopenia-Induced Lymphopenia on Treatment Response and Prognosis in Patients with Stage III Non-Small Cell Lung Cancer: Insights for Optimizing Chemoradiation and Immune Checkpoint Inhibitor.

Sarcopenia is a poor prognostic factor in non-small cell lung cancer (NSCLC). However, its prognostic significance in patients with NSCLC receiving immune checkpoint inhibitors (ICIs) and its relationship with lymphopenia remain unclear. We aimed to investigate the prognostic role of sarcopenia and its effect on lymphocyte recovery in patients with stage III NSCLC treated with concurrent chemoradiotherapy (CCRT) followed by ICI. We retrospectively evaluated 151 patients with stage III NSCLC who received definitive CCRT followed by maintenance ICI between January 2016 and June 2022. Sarcopenia was evaluated by measuring the skeletal muscle area at the L3 vertebra level using computed tomography scans. Lymphocyte level changes were assessed based on measurements taken before and during CCRT and at 1, 2, 3, 6, and 12 months post-CCRT completion. Even after adjusting for baseline absolute lymphocyte count through propensity score-matching, patients with pre-radiotherapy (RT) sarcopenia (n=86) exhibited poor lymphocyte recovery and a significantly high incidence of grade ≥3 lymphopenia during CCRT. Pre-RT sarcopenia and grade ≥3 lymphopenia during CCRT emerged as prognostic factors for overall survival and progression-free survival, respectively. Concurrent chemotherapy dose adjustments, objective response after CCRT, and discontinuation of maintenance ICI were also analyzed as independent prognostic factors. Our results demonstrated an association between pre-RT sarcopenia and poor survival, concurrent chemotherapy dose adjustments, and impaired lymphocyte recovery after definitive CCRT. Moreover, CCRT-induced lymphopenia not only contributed to poor prognosis but may have also impaired the therapeutic efficacy of subsequent maintenance ICI, ultimately worsening treatment outcomes.

Tumor Hyperprogression in Squamous Cell Carcinomas of Head and Neck after Immunotherapy: Our Perspective

Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer worldwide. Although there have been some advances in multimodality therapy, the overall 5-year survival rate remains poor approximately at 40%-50%. Currently, Immune Checkpoint Inhibitor (ICI) based Immunotherapies are being evaluated as an alternate treatment modality for recurrent/metastatic HNSCCs in clinical trials.

A multidimensional analysis of the impact of obesity on immune checkpoint inhibitor therapy efficacy

BackgroundObesity is a well-known risk factor for developing malignant tumors and promoting tumor cell growth and spread. However, recent studies have shown that obese cancer patients, who typically have a worse prognosis than nonobese cancer patients, show a significant improvement in survival after receiving immune checkpoint inhibitor (ICI) therapy. This phenomenon is known as the “obesity paradox”. However, this phenomenon is influenced by tumor type and sex. Therefore, this study aimed to explore the impact of obesity on immunotherapy efficacy from multiple perspectives, aiming to verify this paradox and provide new scientific evidence on the effect of obesity on ICI efficacy.MethodsThis retrospective study evaluated the data of patients who received ICI therapy between June 2019 and August 2023. Automatic segmentation of skeletal muscle, subcutaneous fat, and visceral fat was performed using Slice-O-Matic software, and the corresponding skeletal muscle index (SMI), subcutaneous fat index (SFI) and visceral fat index (VFI) were calculated. The neutrophil-to-lymphocyte ratio (NLR) was determined by dividing the neutrophil count by the lymphocyte count. Univariate and multivariate Cox regression analyses were used to evaluate the correlation between body mass index (BMI), body composition parameters, and the NLR with overall survival (OS) and progression-free survival (PFS) in obese patients receiving ICI therapy.ResultsWe analyzed 219 patients with a median age of 60 years (IQR 53–69 years; 155 men and 64 women). Obese patients, particularly those with visceral fat accumulation, exhibited extended OS after ICI therapy (log­rank P = 0.027). Cox multivariate analysis revealed that the NLR (HR = 1.036; 95% CI: 0.996 to 1.078; P = 0.002) was independently associated with OS. Patients with a high NLR had worse OS than those with a low NLR.ConclusionsThis study corroborates the veracity of the "obesity paradox" under specific conditions and identifies NLR as an independent prognostic factor, with elevated NLR indicative of a poor prognosis.

Fecal Microbiome Composition Correlates with Pathologic Complete Response in Patients with Operable Esophageal Cancer Treated with Combined Chemoradiotherapy and Immunotherapy

Background: Preclinical and clinical data indicate that chemoradiotherapy (CRT) in combination with checkpoint inhibitors may prime an anti-tumor immunological response in esophageal cancer. However, responses to neoadjuvant therapy can vary widely and the key biomarkers to determine response remain poorly understood. The fecal microbiome is a novel and potentially modifiable biomarker of immunotherapy response, and both fecal and tumor microbes have been found to associate with outcomes in esophageal cancer. Methods: Fecal and tumor samples were collected from patients with stage II–III resectable esophageal or gastroesophageal junction carcinoma treated with neoadjuvant immune checkpoint inhibitors (ICIs) plus CRT prior to surgical resection. Microbiome profiles were analyzed by 16S rRNA amplicon sequencing and taxonomic data were integrated with fecal metabolite analysis to assess microbial function. Results: The fecal microbiome of patients with pathological complete response (PCR) grouped in distinct clusters compared to patients with residual viable tumor (RVT) by Bray–Curtis diversity metric. Integrated taxonomic and metabolomic analysis of fecal samples identified a sphingolipid and primary bile acid as enriched in the PCR, the levels of which correlated with several bacterial species: Roseburis inulinivorans, Ruminococcus callidus, and Fusicantenibacter saccharivorans. Analysis of the tumor microbiome profiles identified several bacterial genera previously associated with esophageal tumors, including Streptococcus and Veillonella. Conclusions: These results further characterize the fecal and tumor microbiome of patients with operable esophageal cancer and identify specific microbes and metabolites that may help elucidate how microbes contribute to tumor response with neoadjuvant CRT combined with ICI.

Suppression of melanoma by mice lacking MHC-II: Mechanisms and implications for cancer immunotherapy.

Immune checkpoint inhibitors interfere with T cell exhaustion but often fail to cure or control cancer long-term in patients. Using a genetic screen in C57BL/6J mice, we discovered a mutation in host H2-Aa that caused strong immune-mediated resistance to mouse melanomas. H2-Aa encodes an MHC class II α chain, and its absence in C57BL/6J mice eliminates all MHC-II expression. H2-Aa deficiency, specifically in dendritic cells (DC), led to a quantitative increase in type 2 conventional DC (cDC2) and a decrease in cDC1. H2-Aa-deficient cDC2, but not cDC1, were essential for melanoma suppression and effectively cross-primed and recruited CD8 T cells into tumors. Lack of T regulatory cells, also observed in H2-Aa deficiency, contributed to melanoma suppression. Acute disruption of H2-Aa was therapeutic in melanoma-bearing mice, particularly when combined with checkpoint inhibition, which had no therapeutic effect by itself. Our findings suggest that inhibiting MHC-II may be an effective immunotherapeutic approach to enhance immune responses to cancer.

Defining the optimal setting for transcriptomic analyses on blood samples for response prediction in immunotherapy-treated NSCLC patients

Transcriptomic profiling of blood immune cells offers a promising alternative to invasive, sampling bias-prone tissue-based biomarker assays for predicting immune checkpoint inhibitor (ICI) therapy response in non-small cell lung cancer (NSCLC) patients. However, the optimal analytical approach to identify systemic correlates of response still needs to be explored. We collected peripheral blood mononuclear cells and whole blood (WB) samples from 33 ICI-treated NSCLC patients before ICI treatment and at the first response evaluation. After bulk polyadenylated RNA-sequencing, we assessed differences in gene expression profiles between non-responders and responders using differential expression analysis, single sample gene set enrichment analysis (ssGSEA), and cell type deconvolution. We evaluated gene expression values, ssGSEA scores, and deconvolved cell type proportions to distinguish non-responders from responders via ROC curve (AUC) analysis, training a logistic regression classification model. Gene expression values and deconvolved proportions yielded the best results with WB samples after treatment (AUC = 0.87 and 0.85, respectively). Overall, ssGSEA scores showed superior classification performance across all sample types and timepoints (AUC > 0.7). In conclusion, transcriptomic analysis through ssGSEA demonstrated the best performance as a non-invasive biomarker for predicting clinical benefit in ICI-treated NSCLC patients, with gene expression and deconvolution on post-treatment WB samples also showing promising results.

Predicting survival benefits of immune checkpoint inhibitor therapy in lung cancer patients: a machine learning approach using real-world data.

Due to the heterogeneity in the effectiveness of immunotherapy for lung cancer, identifying predictors is crucial. This study aimed to develop a machine learning model to identify predictors of overall survival in lung cancer patients treated with immune checkpoint inhibitors (ICIs). A retrospective analysis was performed on data from 1314 lung cancer patients at the Chongqing University Cancer Hospital from September 2018 to September 2022. We used the random survival forest (RSF) model to identify survival-influencing factors, using backward elimination for variable selection. A Cox proportional hazards (CPH) model was constructed using the most significant predictors. We assessed model performance and generalizability using time-dependent receiver operating characteristics (ROC) and predictive error curves. The RSF model demonstrated better predictive accuracy than the CPH (IBS 0.17 vs. 0.17; C-index 0.91 vs. 0.68), with better discrimination and prediction performance. The influential variables identified included D-dimer, Karnofsky performance status, albumin, surgery, TNM stage, platelet count, and age. The RSF model, which incorporated these variables, achieved area under the curve (AUC) scores of 0.95, 0.94, and 0.98 for 1-, 3-, and 5-year survival predictions, respectively, in the training set. The validation set showed AUCs of 0.94, 0.90, and 0.95, respectively, exceeding the performance of the CPH model. The study successfully developed a machine learning model that accurately predicted the survival benefits of ICI therapy in lung cancer patients, supporting clinical decision-making in lung cancer treatment.

WNT/β-catenin Signaling and CD8+ Tumor-infiltrating Lymphocytes in Tremelimumab Plus Durvalumab for Advanced Hepatocellular Carcinoma.

Tremelimumab plus durvalumab is an approved first-line therapy for advanced hepatocellular carcinoma (HCC). Previous studies identified WNT/β-catenin mutations or CD8+ tumor-infiltrating lymphocytes (TILs) as biomarkers that can predict responsiveness to immune checkpoint inhibitor therapy in HCC. However, biomarkers for effectiveness of tremelimumab plus durvalumab in HCC have not been reported. This study investigated whether evaluation of WNT/β-catenin signaling and CD8+ TILs by immunohistochemical staining of tumor biopsy tissues can predict the response to tremelimumab plus durvalumab in patients with HCC. Fifteen HCC patients who underwent tumor biopsies were classified into three groups based on WNT/β-catenin signal activation and CD8+ TIL infiltration. The clinical responses to treatment in the groups were evaluated. Four patients had HCC with WNT/β-catenin signal inactivation and high-level CD8+ TIL infiltration, four patients had HCC with WNT/β-catenin signal activation and low-level CD8+ TIL infiltration, and seven patients had WNT/β-catenin signal activation and high-level CD8+ TIL infiltration or WNT/β-catenin signal inactivation and low-level CD8+ TIL infiltration. A better response rate was observed in the WNT/β-catenin signal inactivation and high-level CD8+ TIL infiltration group, and a worse response rate was observed in the WNT/β-catenin signal activation and low-level CD8+ TIL infiltration group. Although the present study involved a small number of patients, the findings suggest that the efficacy of tremelimumab plus durvalumab may be affected by WNT/β-catenin signaling and CD8+ TIL infiltration.

SpliceMutr enables pan-cancer analysis of splicing-derived neoantigen burden in tumors.

Aberrant alternative splicing can generate neoantigens, which can themselves stimulate immune responses and surveillance. Previous methods for quantifying splicing-derived neoantigens are limited by independent references and potential batch effects. Here, we introduce SpliceMutr, a bioinformatics approach and pipeline for identifying splicing derived neoantigens from tumor and normal data. SpliceMutr facilitates the identification of tumor-specific antigenic splice variants, predicts MHC-binding affinity, and estimates splicing antigenicity scores per gene. By applying this tool to genomic data from The Cancer Genome Atlas (TCGA), we generate splicing-derived neoantigens and neoantigenicity scores per sample and across all cancer types and find numerous correlations between splicing antigenicity and well-established biomarkers of anti-tumor immunity. Notably, carriers of mutations within splicing machinery genes have higher splicing antigenicity, which provides support for our approach. Further analysis of splicing antigenicity in cohorts of melanoma patients treated with mono- or combined immune checkpoint inhibition suggests that the abundance of splicing antigens is reduced post-treatment from baseline in patients who progress. We also observe increased splicing antigenicity in responders to immunotherapy, which may relate to an increased capacity to mount an immune response to splicing-derived antigens. We find the splicing antigenicity to be higher in tumor samples when compared to normal, that mutations in the splicing machinery result in increased splicing antigenicity in some cancers, and higher splicing antigenicity is associated with positive response to immune checkpoint inhibitor therapies. Further, this new computational pipeline provides novel analytical capabilities for splicing antigenicity and is openly available for further immuno-oncology analysis.

Disrupting Intracellular Homeostasis by Copper-Based Nanoinducer with Multiple Enzyme-Mimicking Activities to Induce Disulfidptosis-Enhanced Pyroptosis for Tumor Immunotherapy.

Given the crucial role of abnormal homeostasis in tumor cells for maintaining their growth, it may be more efficient with less effort to develop anti-tumor strategies that target multiple combined mechanisms by disrupting intracellular homeostasis. Here, a copper-based nanoinducer (CGBH NNs) with multiple enzyme-like activities is designed and constructed to induce disulfidptosis-enhanced pyroptosis through disrupting multiple intracellular homeostasis for effective tumor immunotherapy. Within the tumor microenvironment (TME), CGBH NNs can disrupt intracellular glucose homeostasis and inhibit NADPH production, leading to accumulation of cystine, which further blocked the substrate and key enzyme for synthesizing glutathione. Subsequently, through cascade catalytic reactions involving enzyme activities (glutathione peroxidase-like, glucose oxidase and peroxidase-like activities), CGBH NNs can produce massive reactive oxygen species(ROS) and further disrupt intracellular redox homeostasis, resulting in the disulfidptosis-enhanced pyroptosis. The tumor cells undergoing immunogenic pyroptosis can release various cytosolic contents and inflammatory factors, eliciting robust immune responses by facilitating immune cell infiltration, and reprogramming the immunosuppressive TME. After the combination with immune checkpoint blockade therapy, CGBH NNs can effectively suppress the tumor growth and prolong the survival time of tumor-bearing mice. This work presents a novel paradigm to trigger disulfidptosis-enhanced pyroptosis by destroying intracellular homeostasis for anti-tumor immunotherapy.

Diagnostic and prognostic significance of tetraspanin 6 and its role in facilitating glioma progression

BackgroundSeveral tetraspanin (TSPAN) proteins have been implicated in tumorigenesis and disease progression. However, the precise function of tetraspanin 6 (TSPAN6) in glioma remains unclear.MethodsIntegrated raw data from the Tumor Genome Atlas (TCGA) and Gene Expression Profiling (GEO) databases were processed using R4.2.1. Bioinformatic methods were used to analyze the gene expression levels of TSPAN6 in both glioma and normal brain tissues, correlating them with clinical characteristics. Additionally, the predictive value of TSPAN6 in relation to the immune checkpoint blockade (ICB) therapy response was assessed. In vitro experiments were conducted to investigate the effects of TSPAN6 knockdown on glioma cell proliferation, migration, cell cycle regulation, and macrophage recruitment.ResultsTSPAN6 expression was significantly upregulated in glioma tissues compared to normal tissues. Elevated TSPAN6 expression is strongly correlated with unfavorable clinical characteristics in gliomas. Bioinformatic analyses revealed a significant correlation between elevated TSPAN6 expression and reduced overall survival. Additionally, TSPAN6 was co-expressed with several immune checkpoint genes and revealed a prognostic value in the context of ICB therapy. Functional enrichment analysis revealed the involvement of TSPAN6 in cell-cycle regulation. Furthermore, TSPAN6 expression positively correlated with macrophage and neutrophil infiltration. In vitro experiments confirmed that the downregulation of TSPAN6 inhibited U251 cell proliferation, disrupted the cell cycle, diminished migratory capabilities, and reduced the recruitment of macrophages.ConclusionOur findings emphasize its potential as both a diagnostic and therapeutic target as well as a predictor of immune therapy response in gliomas.

The Application of CRISPR/Cas9 in Cancer Immunotherapy

Currently, Cancer is the number one killer of human health. The death rate from cancer is increasing year over year as the population ages and grows, particularly since 2019, when there were almost 10 million cases globally recorded by the World Health Organization every year. In light of this trend, it is imperative to continue developing medications and to update and iterate on anti-cancer therapeutic technologies. CAR-T cell therapy, microphage-based therapy, oncolytic virotherapy, and checkpoint blockade therapy are the most popular cancer treatments, but a few patients still cannot tolerate these therapies. A post-optimized strategy is to use gene editing to alter the characteristics of cancer treatment. New therapeutic options for the treatment of complex disorders have become available with the development of CRISPR/Cas9 gene editing technology in recent years. This method is widely used in market research for gene knockdown, endogenous gene expression, and chromosome locus markers because of its accuracy and efficiency in processing harmful gene fragments. Also, it is extremely valuable from a medical standpoint when researching immunomodulator resistance. Despite its great potential, there remain concerns over the technology’s usefulness and efficacy and negative prognostic reactions. This review primarily focuses on the current use of CRISPR/Cas9 in cancer immunotherapies.