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Exposure to ionizing radiation, a physical treatment that inactivates live tumor cells, has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human clinical trials. However, the mechanisms by which irradiated cells function as immunogenic tumor vaccines and induce effective antitumor responses have not been fully explored. Here, we demonstrate that oxidized mitochondrial DNA (mtDNA) and stimulator of interferon genes (STING) signaling play a key roles in the enhanced antitumor effect achieved with an irradiated tumor cell vaccine. Elevations in ROS and oxidized mtDNA 8-OHG content could be induced in irradiated tumor cells. Oxidized mtDNA derived from irradiated tumor cells gained access to the cytosol of dendritic cells (DCs). Oxidized mtDNA, as a DAMP or adjuvant, activated the STING-TBK1-IRF3-IFN-β pathway in DCs, which subsequently cross-presented irradiated tumor cell-derived antigens to CD8+ T cells and elicited antitumor immunity. The results of our study provide insight into the mechanism by which an irradiated cell vaccine mediates antitumor immunity, which may have implications for new strategies to improve the efficacy of irradiated vaccines.

The prevalency of lung disease has increased worldwide, especially in the aging population. It is essential to develop novel disease models, that are superior to traditional models. Organoids are three-dimensional (3D) in vitro structures that produce from self-organizing and differentiating stem cells, including pluripotent stem cells (PSCs) or adult stem cells (ASCs). They can recapitulate the in vivo cellular heterogeneity, genetic characteristics, structure, and functionality of original tissues. Drug responses of patient-derived organoids (PDOs) are consistent with that of patients, and show correlations with genetic alterations. Thus, organoids have proven to be valuable in studying the biology of disease, testing preclinical drugs and developing novel therapies. In recent years, organoids have been successfully applied in studies of a variety of lung diseases, such as lung cancer, influenza, cystic fibrosis, idiopathic pulmonary fibrosis, and the recent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. In this review, we provide an update on the generation of organoid models for these diseases and their applications in basic and translational research, highlighting these signs of progress in pathogenesis study, drug screening, personalized medicine and immunotherapy. We also discuss the current limitations and future perspectives in organoid models of lung diseases.

The cell identity of malignant cells and how they acquire it are fundamental for our understanding of cancer. Here, we report that esophageal squamous cell carcinoma (ESCC) cells display molecular features equally similar but distinct to all three types of normal esophageal epithelial cells, which we term as confused cell identity (CCI). CCI is an independent prognostic marker associated with poor prognosis in ESCC. Further, we identify tropomyosin 4 (TPM4) as a critical CCI gene that promotes the aggressiveness of ESCC in vitro and in vivo. And TPM4 creates CCI through activating the Jak/STAT-SOX2 pathway. Thus, our study suggests an unrecognized feature of ESCC cells, which might be of value for clinic prognosis and potential interference.

In this study, we aimed to elucidate the role of PBMC gene expression in ICI treatment response and prognosis. According to Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST version 1.1), patients with no disease progression (PD) or tumor-induced deaths within 6 months of anti-PD-1/PD-L1 treatment, including those with complete response (CR), partial response (PR), or stable disease (SD), were grouped as ICI responders. Currently, the cause-and-effect relationship is not fully understood; however, our study proposes that the loss of chromosome Y (LOY) or extreme downregulation of chromosome Y (EDY) in immune cells may lead to a decrease in the proportion of lymphocytes, thereby resulting in primary resistance to PD-1/PD-L1 blockade immunotherapy. [...]DDX3Y and USP9Y emerge as useful biomarkers for predicting PD-1/PD-L1 blockade response.

The incidence and risk factors of acute kidney injury (AKI) in patients with malignancies receiving immune checkpoint inhibitors (ICIs) are being extensively reported with their widespread application. This study aimed to quantify the incidence and identify risk factors of AKI in cancer patients treated with ICIs. We searched the electronic databases of PubMed/Medline, Web of Science, Cochrane and Embase before 1 February 2023 on the incidence and risk factors of AKI in patients receiving ICIs and registered the protocol in PROSPERO (CRD42023391939). A random-effect meta-analysis was performed to quantify the pooled incidence estimate of AKI, identify risk factors with pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) and investigate the median latency period of ICI-AKI in patients treated with ICIs. Assessment of study quality, meta-regression, and sensitivity and publication bias analyses were conducted. In total, 27 studies consisting of 24048 participants were included in this systematic review and meta-analysis. The overall pooled incidence of AKI secondary to ICIs was 5.7% (95% CI: 3.7%-8.2%). Significant risk factors were older age (OR: 1.01, 95% CI: 1.00-1.03), preexisting chronic kidney disease (CKD) (OR: 2.90, 95% CI: 1.65-5.11), ipilimumab (OR: 2.66, 95% CI: 1.42-4.98), combination of ICIs (OR: 2.45, 95% CI: 1.40-4.31), extrarenal immune-related adverse events (irAEs) (OR: 2.34, 95% CI: 1.53-3.59), and proton pump inhibitor (PPI) (OR: 2.23, 95% CI: 1.88-2.64), nonsteroidal anti-inflammatory drug (NSAID) (OR: 2.61, 95% CI: 1.90-3.57), fluindione (OR: 6.48, 95% CI: 2.72-15.46), diuretic (OR: 1.78, 95% CI: 1.32-2.40) and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) (pooled OR: 1.76, 95% CI: 1.15-2.68) use. Median time from ICIs initiation to AKI was 108.07 days. Sensitivity and publication bias analyses indicated robust results for this study. The occurrence of AKI following ICIs was not uncommon, with an incidence of 5.7% and a median time interval of 108.07 days after ICIs initiation. Older age, preexisting chronic kidney disease (CKD), ipilimumab, combined use of ICIs, extrarenal irAEs, and PPI, NSAID, fluindione, diuretics and ACEI/ARB use are risk factors for AKI in patients receiving ICIs. https://www.crd.york.ac.uk/prospero/, identifier CRD42023391939.

Tumor organoids recapitulate pathological properties and would serve as an excellent ex vivo model for drug discovery. Here, we performed an unbiased drug screening on drivers-defined tumor organoids from mouse endometrial cancer, the most prevalent gynecological malignancy in human, with a small molecule library targeting epigenetic factors. Among them, menin-MLL inhibitors MI-136 and MI-463 scored. The therapeutic capacity of MI-136 was further validated in tumor organoids in vitro and an orthotopic model in vivo. CRISPR/cas9-mediated mutations of major components of the menin-MLL complex, Men1, Kmt2a and Ash2l, inhibited the growth of tumor organoids, suggesting that the complex was the target of MI-136. Transcriptome analysis showed that the hypoxia-inducible factor (HIF) pathway was the most significantly downregulated pathway by MI-136 treatment. Consistently, Men1, Kmt2a, and Ash2l knockout also repressed the expressions of the HIF target genes. Loss of Hif1a or Hif1b partially phenocopied the inhibition of the menin-MLL complex by MI-136 or mutations in term of tumor organoid growth. Further, we found that MEN1 was upregulated in human endometrial cancers, which were tightly correlated with the expression levels of HIF1A, and associated with poor prognosis. Importantly, MI-136 also significantly inhibited the growth of endometrial cancer organoids derived from patients. Thus, our study identified MI-136 as a potential inhibitor for endometrial cancer through regulating the HIF pathway, a novel molecular mechanism distinguished from those in AML and prostate cancer.

The study, published in Nature, incorporates click chemistry into global run-on and sequencing (GRO-seq) to create a single-cell GRO-seq (scGRO-seq) technique.1 This method allows for the precise capture of the episodic and coordinated nature of transcription at high resolution, revealing critical dynamics such as burst size and enhancer-gene interactions. Enhancers, specific to cell types and states, regulate genes over long distances and are often linked to disease regions, making them potential targets for cancer therapies.2 Current genomic tools provide insights into gene activation precursors but lack real-time transcription event capture. scGRO-seq addresses this gap, offering a dynamic view of regulatory mechanisms for targeted cancer treatment. Focusing on a 10 kb central gene region and excluding the ends with paused polymerases, it utilizes an RNA Polymerase II elongation rate of 2.5 kb/min, limiting the burst detection window to just 4 min. Through stringent analysis within a 4-min window, it was found that only 0.7% of over 112 million gene pairs tested were significantly co-transcribed, forming a network of 59 distinct modules with roles in cell cycle regulation, RNA splicing, and DNA repair.

This study delves into the landscape of RNA modification (RM)-related long non-coding RNAs (lncRNAs) within non-small cell lung cancer (NSCLC). We aim to uncover their significance in cancer biology and potential clinical implications. We utilized diverse datasets to identify 444 RM-related genes with 12 RMs. RM scores were computed, and associations with survival were analyzed. Weighted gene co-expression network analysis identified 730 RM-related lncRNAs. Univariate Cox regression identified 63 prognostically significant lncRNAs, leading to the classification of NSCLC samples into two clusters. Distinct differences in overall survival and disease-free interval were observed between the identified lncRNA clusters, showcasing their prognostic relevance. Molecular characterization uncovered mutation landscape variations, with cluster 2 displaying higher mutation rates in TP53 and TTN. Cluster-specific genomic alterations, immune cell infiltration, and immune checkpoint gene expression patterns were identified. Drug sensitivity analysis revealed distinct profiles, with cluster 1 showing potential resistance to a combined approach of certain chemotherapy and immunotherapy, while cluster 2 may be suitable for monotherapy with specific chemotherapeutic or targeted agents. In conclusion, this study stands as the first and most comprehensive exploration, elucidating the intricate connections between RM, lncRNAs, NSCLC, and tumor immunity. Its findings significantly enhance our comprehension of NSCLC heterogeneity, offering pivotal insights and paving the path toward personalized treatment strategies.

Gastric Squamous Cell Carcinoma (GSCC) is a rare but aggressive subtype of gastric cancer with unique histopathology, whose etiology remains poorly understood. Here, we perform genomics analyses of twenty GSCC samples and find that epigenetic regulation genes are among the most frequently mutated genes, including Enhancer of zeste homolog 2 ( EZH2 ). Ezh2 loss induces squamous feature both in gastric organoids in vitro and in vivo mouse model. Ezh2 deficiency, together with Trp53 and Pten loss, both of which are also frequently mutated in GSCC, give rise to full-blown GSCC in mice. Mechanistically, we find that Ezh2 could repress the expression of Transcription factor AP-2 gamma ( Tfap2c ), a transcription factor with the ability to initiate epidermal squamous differentiation, through H3K27 methylation. Disruption of Tfap2c reduces the squamous characteristics of the Ezh2 loss-driven GSCC and reverses its resistance to chemo treatment. Our findings elucidate key molecular mechanisms underlying GSCC pathogenesis and identify potential therapeutic targets for this aggressive malignancy. Gastric Squamous Cell Carcinoma (GSCC) is a rare subtype of gastric cancer with unknown etiology. Here, the authors identify frequent mutations in epigenetic regulation genes including EZH2 in twenty GSCC patient samples, and demonstrate that EZH2 loss, along with TP53 and PTEN loss, leads to GSCC in mouse models.

Angiogenesis and inflammation are crucial processes through which the tumor microenvironment (TME) influences tumor progression. In this study, we showed that peroxisome proliferator‐activated receptor γ (PPARγ) is not only expressed in CT26 and 4T1 tumor cell lines but also in cells of TME, including endothelial cells and tumor‐associated macrophages (TAM). In addition, we showed that rosiglitazone may induce tumor vessel normalization and reduce TAM infiltration. Additionally, 4T1 and CT26 tumor‐bearing mice treated with rosiglitazone in combination with radiotherapy showed a significant reduction in lesion size and lung metastasis. We reported that a single dose of 12 Gy irradiation strongly inhibits local tumor angiogenesis. Secretion of C‐C motif chemokine ligand 2 (CCL2) in response to local irradiation facilitates the recruitment of migrating CD11b+ myeloid monocytes and TAM to irradiated sites that initiate vasculogenesis and enable tumor recurrence after radiotherapy. We found that rosiglitazone partially decreases CCL2 secretion by tumor cells and reduces the infiltration of CD11b+ myeloid monocytes and TAM to irradiated tumors, thereby delaying tumor regrowth after radiotherapy. Therefore, combination of the PPARγ agonist rosiglitazone with radiotherapy enhances the effectiveness of radiotherapy to improve local tumor control, decrease distant metastasis risks and delay tumor recurrence. Rosiglitazone may promote normalization of the tumor vasculature and limit TAM infiltration. The synergistic interaction between rosiglitazone and radiotherapy (RT) is evident, which indicates this combination as a powerful antitumor treatment. Rosiglitazone, as an adjuvant therapy to RT, inhibits CCL2‐mediated tumor recurrence by reducing the recruitment of CD11b+ myeloid monocytes and TAM and consequent vasculogenesis.