The response rate of pancreatic cancer to chemotherapy or immunotherapy pancreatic cancer is low. Although minimally invasive irreversible electroporation (IRE) ablation is a promising option for irresectable pancreatic cancers, the immunosuppressive tumour microenvironment that characterizes this tumour type enables tumour recurrence. Thus, strengthening endogenous adaptive antitumour immunity is critical for improving the outcome of ablation therapy and post-ablation immune therapy. Here we present a hydrogel microsphere vaccine that amplifies post-ablation anti-cancer immune response via releasing its cargo of FLT3L and CD40L at the relatively lower pH of the tumour bed. The vaccine facilitates migration of the tumour-resident type 1 conventional dendritic cells (cDC1) to the tumour-draining lymph nodes (TdLN), thus initiating the cDC1-mediated antigen cross-presentation cascade, resulting in enhanced endogenous CD8⁺ T cell response. We show in an orthotopic pancreatic cancer model in male mice that the hydrogel microsphere vaccine transforms the immunologically cold tumour microenvironment into hot in a safe and efficient manner, thus significantly increasing survival and inhibiting the growth of distant metastases.

Analysis of cell-free DNA (cfDNA) is promising for broad applications in clinical settings, but with significant bias towards late-stage cancers. Although recent studies have discussed the diverse and degraded nature of cfDNA molecules, little is known about its impact on the practice of cfDNA analysis. We developed single-strand library preparation and hybrid-capture-based cfDNA sequencing (SLHC-seq) to analysis degraded cfDNA fragments. Next we used SLHC-seq to perform cfDNA profiling in 112 pancreatic cancer patients, and the results were compared with 13 previous reports. Extensive analysis was performed in terms of cfDNA fragments to explore the reasons for higher detection rate of KRAS mutations in the circulation of pancreatic cancers. By applying the new approach, we achieved higher efficiency in analysis of mutations than previously reported using other detection assays. 791 cancer-specific mutations were detected in plasma of 88% patients with KRAS hotspots detected in 70% of all patients. Only 8 mutations were detected in 28 healthy controls without any known oncogenic or truncating alleles. cfDNA profiling by SLHC-seq was largely consistent with results of tissue-based sequencing. SLHC-seq rescued short or damaged cfDNA fragments along to increase the sensitivity and accuracy of circulating-tumour DNA detection. We found that the small mutant fragments are prevalent in early-stage patients, which provides strong evidence for fragment size-based detection of pancreatic cancer. The new pipeline enhanced our understanding of cfDNA biology and provide new insights for liquid biopsy.

ARID1A is a key mammalian SWI/SNF complex subunit that is mutated in 5% to 11% of lung cancers. Although recent studies have elucidated the mechanism underlying dysregulation of the switch/sucrose non-fermentable (SWI/SNF) complexes in cancers, the significance of ARID1A loss and its implications in lung cancers remain poorly defined. This study investigates how ARID1A loss affects initiation and progression of lung cancer. In genetically engineered mouse models bearing mutant Kras and a deficient Trp53 allele (KP), ARID1A loss (KPA) promoted lung tumorigenesis. Analysis of the transcriptome profiles of KP and KPA tumors suggested enhanced glycolysis following ARID1A loss, and expression of the glycolytic regulators Pgam1, pyruvate kinase M (Pkm), and Pgk1 was significantly increased in ARID1A-deficient lung tumors. Furthermore, ARID1A loss increased chromatin accessibility and enhanced hypoxia-inducible factor-1α (HIF1α) binding to the promoter regions of Pgam1, Pkm, and Pgk1. Loss of ARID1A in lung adenocarcinoma also resulted in loss of histone deacetylase 1 (HDAC1) recruitment, increasing acetylation of histone-4 lysine at the promoters of Pgam1, Pkm, and Pgk1, and subsequently enhancing BRD4-driven transcription of these genes. Metabolic analyses confirmed that glycolysis is enhanced in ARID1A-deficient tumors, and genetic or pharmacologic inhibition of glycolysis inhibited lung tumorigenesis in KPA mice. Treatment with the small molecule bromodomain and extraterminal protein (BET) inhibitor JQ1 compromised both initiation and progression of ARID1A-deficient lung adenocarcinoma. ARID1A negatively correlated with glycolysis-related genes in human lung adenocarcinoma. Overall, ARID1A loss leads to metabolic reprogramming that supports tumorigenesis but also confers a therapeutic vulnerability that could be harnessed to improve the treatment of ARID1A-deficient lung cancer. Significance: This study links ARID1A loss with enhanced glycolysis in lung cancer and demonstrates the preclinical efficacy of BET inhibitor therapy as a strategy to combat tumor growth.

Metabolic reprogramming by oncogenic signaling is a hallmark of cancer. Hyperactivation of Wnt/β-catenin signaling has been reported in hepatocellular carcinoma (HCC). However, the mechanisms inducing hyperactivation of Wnt/β-catenin signaling and strategies for targeting this pathway are incompletely understood. In this study, we find nucleoside diphosphate kinase 7 (NME7) to be a positive regulator of Wnt/β-catenin signaling. Upregulation of NME7 positively correlated with the clinical features of HCC. Knockdown of NME7 inhibited HCC growth in vitro and in vivo, whereas overexpression of NME7 cooperated with c-Myc to drive tumorigenesis in a mouse model and to promote the growth of tumor-derived organoids. Mechanistically, NME7 bound and phosphorylated serine 9 of GSK3β to promote β-catenin activation. Furthermore, MTHFD2, the key enzyme in one-carbon metabolism, was a target gene of β-catenin and mediated the effects of NME7. Tumor-derived organoids with NME7 overexpression exhibited increased sensitivity to MTHFD2 inhibition. In addition, expression levels of NME7, β-catenin, and MTHFD2 correlated with each other and with poor prognosis in patients with HCC. Collectively, this study emphasizes the crucial roles of NME7 protein kinase activity in promoting Wnt/β-catenin signaling and one-carbon metabolism, suggesting NME7 and MTHFD2 as potential therapeutic targets for HCC. Significance: The identification of NME7 as an activator of Wnt/β-catenin signaling and MTHFD2 expression in HCC reveals a mechanism regulating one-carbon metabolism and potential therapeutic strategies for treating this disease.

Pancreatic ductal adenocarcinoma (PDAC) is a "cold" solid tumor with frequent Major Histocompatibility Complex I (MHC-I) deficiency, thereby making it resistant to type-1-conventional dendritic cell (cDC1)-CD8⁺T cell mediated anti-tumor immunity. Current studies have demonstrated the emerging compensatory role of MHC-II-mediated antigen presentation and CD4⁺T cell activation in anti-tumor immunity against MHC-I-deficient tumors. However, the underlying mechanism of the compensatory immune response by CD4⁺T cells in cancer ablation therapy remains to be elucidate. In clinical samples and murine models, we observed that irreversible electroporation (IRE) ablation therapy promoted immune infiltration and the conversion of CD4⁺T cells into anti-tumor IFN-γ⁺Th1 cells and Th17 cells in MHC-I low-expressed PDAC using scRNA-seq and flow-cytometry analyses. Furthermore, we found that PD-L1 blockade predominantly enhanced the activation of CD11b⁺CD103^-type-2 conventional dendritic cells (cDC2s) and their antigen presentation to CD4⁺T cells after ablation, stimulating the anti-tumor immune response through the tumor antigen-specific IFN-γ⁺Th1-NK cell axis. Elevated plasma levels of IL-6 in pancreatic cancer patients receiving ablation therapy are significant indicators for impaired prognosis. IL-6 and PD-L1 dual blockade could significantly augment the ratio of IFN-γ⁺Th1 in CD4⁺T cells to boost the anti-tumor immunity of NK cells, leading to prolonged survival of mouse bearing pancreatic cancer. Collectively, we have elucidated that PD-L1 blockade activates the cDC2-CD4⁺T cell axis after IRE therapy, thereby playing a pivotal compensatory anti-tumor role in MHC-I low-expressed pancreatic cancer. Moreover, a combination strategy involving dual-target blockade of PD-L1/IL-6 along with ablation therapy could emerge as a novel therapeutic approach for MHC-I deficient tumors.

: Actinomycetes is an abundant resource for discovering a large number of lead compounds, which play an important role in microbial drug discovery. Compared to terrestrial microorganisms, marine actinomycetes have unique metabolic pathways because of their special living environment, which has the potential to produce a variety of bioactive substances. In this paper, secondary metabolites isolated from marine actinomycetes are reviewed (2013-2018), most of which exhibited cytotoxic, antibacterial, and antiviral biological activities.