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Background: Non-small-cell lung cancer (NSCLC) with STK11 mutation showed primary resistance to immune checkpoint inhibitors (ICIs). The glucose-lowering drug metformin exerted anti-cancer effect and enhanced efficacy of chemotherapy in NSCLC with KRAS/STK11 co-mutation, yet it is unknown whether metformin may enhance ICI efficacy in STK11 mutant NSCLC.Methods: We studied the impact of metformin on ICI efficacy in STK11 mutant NSCLC in vitro and in vivo using colony formation assay, cell viability assay, Ki67 staining, ELISA, CRISPR/Cas9-mediated knockout, and animal experiments.Results: Through colony formation assay, Ki67 incorporation assay, and CCK-8 assay, we found that metformin significantly enhanced the killing of H460 cells and A549 cells by T cells. In NOD-SCID xenografts, metformin in combination with PD-1 inhibitor pembrolizumab effectively decreased tumor growth and increased infiltration of CD8+ T cells. Metformin enhanced stabilization of STING and activation of its downstream signaling pathway. siRNA-mediated knockdown of STING abolished the effect of metformin on T cell-mediated killing of tumor cells. Next, we found that CRISPR/Cas9-mediated knockout of the scaffold protein AXIN-1 abolished the effect of metformin on T cell-mediated killing and STING stabilization. Immunoprecipitation and confocal macroscopy revealed that metformin enhanced the interaction and colocalization between AXIN-1 and STING. Protein-protein interaction modeling indicated that AXIN-1 may directly bind to STING at its K150 site. Next, we found that metformin decreased K48-linked ubiquitination of STING and inhibited the interaction of E3-ligand RNF5 and STING. Moreover, in AXIN-1−/− H460 cells, metformin failed to alter the interaction of RNF5 and STING.Conclusion: Metformin combining PD-1 inhibitor enhanced anti-tumor efficacy in STK11 mutant lung cancer through inhibition of RNF5-mediated K48-linked ubiquitination of STING, which was dependent on AXIN-1.

Er doped ZnO (EZO) thin films were successfully prepared by sol-gel spin coating method on quartz glass substrates. The effect of Er doping content on the microstructure and optical properties of EZO thin films were investigated. The X-ray diffraction and X-ray photoelectron spectroscopy results indicate that Er was successfully incorporated into the EZO thin films and substituted the Zn sites. The incorporation of Er could affect the band gap (E g ) and optical constants of ZnO thin films. The photoluminescence spectra show that the 1.54 lm emission, which originates from the transition of Er 3? : 4I 13/2 ? 4I 15/2 , was observed in EZO thin films. Furthermore, it is demonstrated that the formation of singly ionized oxygen vacancies (V OÁ ) could be inhibited by the incorporation of Er dopant, which is supported by further defect formation energies calculations.

Background: Circulating tumor DNA (ctDNA) has made a breakthrough as an early biomarker in operable early-stage cancer patients. However, the function of ctDNA combined with cell-free DNA (cfDNA) as a predictor in advanced non-small cell lung cancer (NSCLC) remains unknown. Here, we explored its potential as a biomarker for predicting the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced NSCLC. Methods: A retrospective analysis was undertaken. Plasma collected from 51 patients with advanced NSCLC prior to and serially after starting treatment with EGFR-TKIs was analyzed by next-generation sequencing (NGS). The performance of ctDNA, cfDNA, and combining ctDNA with cfDNA were evaluated for their ability to predict survival outcomes. Results: Patients with early undetectable ctDNA and increasing cfDNA had a markedly better progression-free survival (PFS) (p < 0.001) and overall survival (OS) (p = 0.001) than those with early detectable ctDNA and decreasing cfDNA. Patients with early ctDNA clearance were more likely to have the ctDNA persistent clearance (p = 0.006). The early clearance rate of ctDNA in the normal carcinoembryonic antigen (CEA) group was significantly higher than in the low and high groups (p = 0.028). Patients with greater CEA decline had a higher early clearance rate of ctDNA than those with minor CEA change (p = 0.016). Conclusions: We based this study on ctDNA and cfDNA, explored its prognostic predictive ability, and combined CEA to monitor EGFR-TKI efficacy. This study may provide new perspectives and insights into the precise treatment strategies for NSCLC patients. K E Y W O R D Snon-small cell lung cancer, epidermal growth factor receptor tyrosine kinase inhibitors, circulating tumor DNA, cell-free DNA, carcinoembryonic antigen

Multiple component integration to achieve both therapy and diagnosis in a single theranostic nanosystem has aroused great research interest in the medical investigator. This study aimed to construct a novel theranostic nanoplatform ferrite and ceria co-engineered mesoporous silica nanoparticles (Fe/Ce-MSN) antioxidant agent though a facile metal Fe/Ce-codoping approach in the MSN framework. The resulted Fe3+-incorporated ceria-based MSN nanoparticles possessing a higher Ce3+-to-Ce4+ ratio than those revealed by ceria-only nanoparticles. The as-prepared Fe/Ce-MSN nanoparticles exhibited an excellent efficiency in scavenging reactive oxygen species (ROS), which is attributed to improving the superoxide dismutase (SOD) mimetics activity by increasing Ce3+ content and maintaining a higher activity of catalase (CAT) mimetics via including ferrite ion in nanoparticles. The fast Fe/Ce-MSN biodegradation, which is sensitive to the mild acidic microenvironment of inflammation, can accelerate Fe/Ce ion release, and the freed Fe ions enhanced T2-weighted magnetic resonance imaging in the inflammation site. PEGylated Fe/Ce-MSN nanoparticles in vitro cell models significantly attenuated ROS-induced inflammation, oxidative stress, and apoptosis in macrophages by scavenging overproduced intracellular ROS. More importantly, Fe/Ce-MSN-PEG NPs exhibited significant anti-inflammatory effects by inhibiting lipopolysaccharide (LPS)-induced expression of tumor necrosis factor-α (TNF-α) and interleukin-1 beta (IL-1β) levels in vitro. Additionally, it can promote the macrophages polarization of pro-inflammatory M1 phenotype towards an anti-inflammatory M2 phenotype. Thus, the novel pH-responsive theranostic nanoplatform shows great promise for inflammation and oxidative stress-associated disease treatment.