Liposome-based in situ antigen-modification strategy for "universal" T-cell-receptor engineered T cell in cancer immunotherapy.

T-cell receptor (TCR) engineered T-cell therapy, unlike chimeric antigen receptor T-cell therapy, relies on the inherent ability of TCRs to detect a wider variety of antigenic epitopes, such as protein fragments found internally or externally on cells. Hence, TCR-T-cell therapy offers broader possibilities for treating solid tumors. However, because of the complicated process of identifying specific antigenic peptides, their clinical application still encounters significant challenges. Thus, we aimed to establish a novel "universal" TCR-T "artificial antigen expression" technique that involves the delivery of the antigen to tumor cells using DSPE-PEG-NY-ESO-1157-165 liposomes (NY-ESO-1 Lips) to express TCR-T-cell-specific recognition targets. In vitro as well as in vivo studies revealed that they could accumulate efficiently in the tumor area and deliver target antigens to activate the tumor-specific cytotoxic T-cell immune response. NY-ESO-1 TCR-T therapy, when used in combination, dramatically curbed tumor progression and extended the longevity of mice. Additionally, PD-1 blockage enhanced the therapeutic effect of the aforementioned therapy. In conclusion, NY-ESO-1 Lips "cursed" tumor cells by enabling antigenic target expression on their surface. This innovative technique presents a groundbreaking approach for the widespread utilization of TCR-T in solid tumor treatment.

Identification of hypoxic macrophages in glioblastoma with therapeutic potential for vasculature normalization.

Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients with isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize a Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic niche cues to acquire a hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions by activating adrenomedullin paracrine signaling, thereby stimulating a hyperpermeable neovasculature that hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation or pharmacological blockade of adrenomedullin produced by Hypoxia-TAM restores vascular integrity, improves intratumoral concentration of the anti-tumor agent dabrafenib, and achieves combinatorial therapeutic benefits. Increased proportion of Hypoxia-TAM or adrenomedullin expression is predictive of tumor vessel hyperpermeability and a worse prognosis of glioblastoma. Our findings highlight Mo-TAM diversity and spatial niche-steered Mo-TAM reprogramming in diffuse gliomas and indicate potential therapeutics targeting Hypoxia-TAM to normalize tumor vasculature.

SNAC1-OsERF103-OsSDG705 module mediates drought response in rice.

Drought stress profoundly hampers both plant growth and crop yield. To combat this, plants have evolved intricate transcriptional regulation mechanisms as a pivotal strategy. Through a genetic screening with rice genome-scale mutagenesis pool under drought stress, we identified an APETALA2/Ethylene Responsive Factor, namely OsERF103, positively responds to drought tolerance in rice. Combining chromatin immunoprecipitation sequencing and RNA sequencing analyses, we pinpointed c. 1000 genes directly influenced by OsERF103. Further results revealed that OsERF103 interacts with Stress-responsive NAC1 (SNAC1), a positive regulator of drought tolerance in rice, to synergistically regulate the expression of key drought-related genes, such as OsbZIP23. Moreover, we found that OsERF103 recruits a Su(var)3-9,enhancer of zeste and trithorax-domain group protein 705, which encodes a histone 3 lysine 4 (H3K4)-specific methyltransferase to specifically affect the deposition of H3K4me3 at loci like OsbZIP23 and other genes linked to dehydration responses. Additionally, the natural alleles of OsERF103 are selected during the domestication of both indica and japonica rice varieties and exhibit significant geographic distribution. Collectively, our findings have unfurled a comprehensive mechanistic framework underlying the OsERF103-mediated cascade regulation of drought response. This discovery not only enhances our understanding of drought signaling but also presents a promising avenue for the genetic improvement of drought-tolerant rice cultivars.

Phonon thermal transport in ferroelectricα-In2Se3 via first-principles calculations.

Two-dimensional (2D) ferroelectrics are promising candidates in the field of microelectronics due to their unique properties such as excellent photoelectric responsiveness. However, the thermal properties of 2D ferroelectrics are less investigated. Here, the thickness dependent thermal conductivity in ferroelectricα-In2Se3is systematically investigated by the first-principles method combined with the phonon Boltzmann transport equation. On this basis, the strain and oxidation effects on the thermal conductivity of monolayerα-In2Se3is further studied. The calculation results show that the thermal conductivity has a significant reduction with decreasing film thickness or increasing tensile strain, and the anharmonic phonon-phonon scattering rate is the intrinsic mechanism for the reduction in thermal conductivity. On the other hand, the replacement of Se atoms by O atoms can achieve a bidirectional and wide-range (12×) tuning of thermal conductivity. The increase in specific heat and phonon group velocity is responsible for the thermal conductivity enhancement at high doping levels while that in phonon-phonon scattering rate is responsible for the thermal conductivity reduction at low doping levels. In all cases, acoustic phonons dominate the in-plane thermal transport behavior. These findings broaden our understanding of phonon transport and its control in ferroelectric semiconductorα-In2Se3.

Circular RNA encoded MET variant promotes glioblastoma tumorigenesis.

Activated by its single ligand, hepatocyte growth factor (HGF), the receptor tyrosine kinase MET is pivotal in promoting glioblastoma (GBM) stem cell self-renewal, invasiveness and tumorigenicity. Nevertheless, HGF/MET-targeted therapy has shown limited clinical benefits in GBM patients, suggesting hidden mechanisms of MET signalling in GBM. Here, we show that circular MET RNA (circMET) encodes a 404-amino-acid MET variant (MET404) facilitated by the N6-methyladenosine (m6A) reader YTHDF2. Genetic ablation of circMET inhibits MET404 expression in mice and attenuates MET signalling. Conversely, MET404 knock-in (KI) plus P53 knock-out (KO) in mouse astrocytes initiates GBM tumorigenesis and shortens the overall survival. MET404 directly interacts with the MET ß subunit and forms a constitutively activated MET receptor whose activity does not require HGF stimulation. High MET404 expression predicts poor prognosis in GBM patients, indicating its clinical relevance. Targeting MET404 through a neutralizing antibody or genetic ablation reduces GBM tumorigenicity in vitro and in vivo, and combinatorial benefits are obtained with the addition of a traditional MET inhibitor. Overall, we identify a MET variant that promotes GBM tumorigenicity, offering a potential therapeutic strategy for GBM patients, especially those with MET hyperactivation.

The OsbHLH002/OsICE1-OSH1 module orchestrates secondary cell wall formation in rice.

Transcriptional regulation of secondary cell wall (SCW) formation is strictly controlled by a complex network of transcription factors in vascular plants and has been shown to be mediated by a group of NAC master switches. In this study, we show that in a bHLH transcription factor, OsbHLH002/OsICE1, its loss-of-function mutant displays a lodging phenotype. Further results show that OsbHLH002 and Oryza sativa homeobox1 (OSH1) interact and share a set of common targets. In addition, the DELLA protein SLENDER RICE1, rice ortholog of KNOTTED ARABIDOPSIS THALIANA7, and OsNAC31 interact with OsbHLH002 and OSH1 and regulate their binding capacity on OsMYB61, a key regulatory factor in SCW development. Collectively, our results indicate OsbHLH002 and OSH1 as key regulators in SCW formation and shed light on molecular mechanisms of how active and repressive factors precisely orchestrate SCW synthesis in rice, which may provide a strategy for manipulating plant biomass production.

The OsFTIP6-OsHB22-OsMYBR57 module regulates drought response in rice.

Plants have evolved a sophisticated set of mechanisms to adapt to drought stress. Transcription factors play crucial roles in plant responses to various environmental stimuli by modulating the expression of numerous stress-responsive genes. However, how the crosstalk between different transcription factor families orchestrates initiation of the key transcriptional network and the role of posttranscriptional modification of transcription factors, especially in cellular localization/trafficking in response to stress in rice, remain still largely unknown. In this study, we isolated an Osmybr57 mutant that displays a drought-sensitive phenotype through a genetic screen for drought stress sensitivity. We found that OsMYBR57, an MYB-related protein, directly regulates the expression of several key drought-related OsbZIPs in response to drought treatment. Further studies revealed that OsMYBR57 interacts with a homeodomain transcription factor, OsHB22, which also plays a positive role in drought signaling. We further demonstrate that OsFTIP6 interacts with OsHB22 and promotes the nucleocytoplasmic translocation of OsHB22 into the nucleus, where OsHB22 cooperates with OsMYBR57 to regulate the expression of drought-responsive genes. Our findings have revealed a mechanistic framework underlying the OsFTIP6-OsHB22-OsMYBR57 module-mediated regulation of drought response in rice. The OsFTIP6-mediated OsHB22 nucleocytoplasmic shuttling and OsMYBR57-OsHB22 regulation of OsbZIP transcription ensure precise control of expression of OsLEA3 and Rab21, and thereby regulate the response to water deficiency in rice.

Nuclear translocation of OsMFT1 that is impeded by OsFTIP1 promotes drought tolerance in rice.

Drought is the leading environmental threat affecting crop productivity, and plants have evolved a series of mechanisms to adapt to drought stress. The FT-interacting proteins (FTIPs) and phosphatidylethanolamine-binding proteins (PEBPs) play key roles in developmental processes, whereas their roles in the regulation of stress response are still largely unknown. Here, we report that OsFTIP1 negatively regulates drought response in rice. We showed that OsFTIP1 interacts with rice MOTHER OF FT AND TFL1 (OsMFT1), a PEBP that promotes rice tolerance to drought treatment. Further studies discovered that OsMFT1 interacts with two key drought-related transcription factors, OsbZIP66 and OsMYB26, regulating their binding capacity on drought-related genes and thereby enhancing drought tolerance in rice. Interestingly, we found that OsFTIP1 impedes the nucleocytoplasmic translocation of OsMFT1, implying that dynamic modulation of drought-responsive genes by the OsMFT1-OsMYB26 and OsMFT1-OsbZIP66 complexes is integral to OsFTIP1-modulated nuclear accumulation of OsMFT1. Our findings also suggest that OsMFT1 might act as a hitherto unknown nucleocytoplasmic trafficking signal that regulates drought tolerance in rice in response to environmental signals.