Core Insights - The article discusses T cell exhaustion as a critical mechanism in cancer immunotherapy resistance, highlighting the role of a specific stress response called Tex-PSR [3][4][10] Group 1: T Cell Exhaustion Mechanism - T cell exhaustion (Tex) is characterized by reduced effector function and increased expression of inhibitory receptors, driven by persistent antigen exposure and adverse microenvironments [3] - The study identifies a unique stress response, Tex-PSR, which is triggered by the accumulation of misfolded proteins, leading to T cell exhaustion and immune evasion [4][9] Group 2: Research Findings - The research provides a comprehensive protein landscape of Tex cells under various conditions, revealing inconsistencies between mRNA transcription levels and protein expression [7][8] - Tex-PSR is marked by increased global protein synthesis, unlike the classical unfolded protein response (UPR), which typically inhibits protein synthesis [8][13] Group 3: Clinical Implications - The findings suggest that targeting the Tex-PSR pathway could represent a new direction for cancer immunotherapy, potentially improving T cell vitality and reversing exhaustion [10][12] - The study indicates that the Tex-PSR characteristics are also present in exhausted T cells from human cancer patients, correlating with poor clinical responses to immunotherapy [9][10]

Core Insights - The article highlights the significant contributions of Chinese scholars in top international academic journals, with 8 out of 18 papers published in Nature on October 1, 2025, authored by Chinese researchers [2][5][6][7][8][10][12][14]. - A notable paper from Yale University discusses a new method in spatial transcriptomics, RAEFISH, which achieves whole-genome coverage and single-molecule resolution, marking a significant advancement in the field [16][19]. - A study from the National Laboratory of Yacheng Bay reveals the genetic selection trajectories in soybean domestication, providing new insights into breeding strategies and genetic resources [20][23][24]. Group 1: Contributions to Nature - On October 1, 2025, multiple papers authored by Chinese scholars were published in Nature, including significant studies on T cell exhaustion, dietary impacts on intestinal stemness, and new paradigms in protein biogenesis [2][5][6][7][8][10]. - The research from Ohio State University on T cell exhaustion highlights the role of proteotoxic stress in immune evasion [2]. - The study from MIT explores how dietary cysteine enhances intestinal stemness through CD8 T cell-derived IL-22 [5]. Group 2: Innovations in Spatial Transcriptomics - The Yale University team developed RAEFISH, a new spatial transcriptomics method that allows for whole-genome coverage and single-molecule resolution, addressing previous limitations in the field [16][19]. - This advancement provides a powerful tool for various biological research areas, including developmental biology and drug discovery [19]. Group 3: Soybean Genetic Research - The research team at Yacheng Bay National Laboratory studied 8,105 soybean accessions, revealing key genetic selections during domestication and improvement processes [20][23]. - The findings indicate the existence of two independent centers of soybean domestication and highlight the importance of black soybean in this process [23]. - The study also provides insights into the changing breeding priorities in China, emphasizing high protein content in the early years and more recently focusing on yield, oil content, and stress resistance [23][24].

Core Insights - The article discusses the domestication, dissemination, and improvement trajectories of soybean, highlighting its significance as a major source of protein and oil for human consumption and animal feed [3][4][6]. Group 1: Research Findings - The study analyzed genomic information from 8,105 soybean accessions, including wild types, local varieties, and modern cultivars, revealing the genetic selection trajectories during domestication and improvement [4][6]. - Black soybean is identified as a key intermediate type in the domestication process, with findings suggesting that domestication traits were selected gradually [6][7]. - The research proposes the existence of two independent centers of soybean domestication in China: one in the Huang-Huai-Hai region and another in the northwest [6][7]. Group 2: Implications for Breeding - The study provides new molecular targets for future soybean quality improvement by identifying selected genes that facilitated trait enhancement and environmental adaptation during global dissemination [6][9]. - It highlights the shift in breeding focus in China from high-protein soybean varieties in the early years to an emphasis on high yield, high oil content, and stress resistance in recent years [6][9]. - A high-density soybean genome variation map and quantitative trait nucleotide (QTN) database were established, providing valuable resources for the global research community [7][9].

Core Viewpoint - The article discusses a groundbreaking DNA synthesis technology called mMPS, developed by BGI Life Sciences Research Institute, which overcomes traditional limitations in DNA synthesis efficiency, cost, and coverage, marking a significant advancement in synthetic biology [3][4][6]. Group 1: Technology Overview - mMPS technology utilizes a microchip-based approach, dividing a chip into independent millimeter-scale microchips, each synthesizing a single short DNA strand, allowing for identity tracking and sorting of DNA fragments [7][9]. - The technology enables a systematic breakthrough in synthesis throughput, yield, and quality, addressing the challenges of traditional high-throughput DNA synthesis methods [3][10]. Group 2: Performance and Applications - mMPS technology has demonstrated superior performance in complex sequence handling, high GC content regions, and repetitive sequences, providing reliable support for protein stability research and disease mutation mechanism analysis [10]. - The technology significantly reduces the time for constructing mutation libraries from weeks to days, enhancing the discovery and optimization process of antibody drugs [12]. - In the field of clinical diagnostics, mMPS can synthesize thousands of primer probes at once, reducing costs by over three times and enabling upgrades in multi-target detection capabilities [13]. Group 3: Industrial Impact - The mMPS technology is expected to transform DNA synthesis from a laboratory service into a foundational infrastructure for biomanufacturing, driving efficiency revolutions in pharmaceuticals and diagnostics [12]. - The cost of single-base synthesis is reduced by approximately 70% compared to traditional methods, facilitating large-scale industrial applications [12]. - The modular and automated characteristics of mMPS technology lay the groundwork for the emergence of "DNA synthesis as a service" platforms, integrating AI-driven design and automated synthesis [15]. Group 4: Future Prospects - The mMPS technology is anticipated to become the core engine of next-generation industrial-grade DNA synthesis factories, enabling the design, construction, and testing of complex biological systems [18]. - Experts believe that the integration of AI and automation with mMPS will drive deep integration and industrialization of synthetic biology in biomanufacturing and healthcare [18].

Core Insights - Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults, with a median survival of only 12-18 months post-diagnosis, and current treatments have limited efficacy in extending life expectancy [2][3] - A recent study published by Zhao Wei's team in Nature Cell Biology identifies HOXB3 condensation in the core regulatory circuitry (CRC) of GBM as a potential therapeutic target, suggesting that targeting HOXB3 with the peptide P621-R9 can selectively reduce tumorigenic potential in patient-derived xenograft models [2][5] Research Findings - The study utilized single-cell CUT&Tag analysis to investigate H3K27ac modifications, revealing significant heterogeneity within the GBM core regulatory circuitry [5] - The research highlighted the heterogeneous condensation state of HOXB3, influenced by its intrinsic disordered region (IDR) and interaction with RUNX1, which drives phenotypic expression [5] - The synthesized peptide P621-R9 effectively disrupts HOXB3 condensation, alters chromatin structure, and reduces transcription at super-enhancer-associated oncogenic loci in GBM cells exhibiting HOXB3 condensation [5][6] Implications for Treatment - These findings underscore the critical role of condensation in the heterogeneity of GBM and suggest that peptide-based targeted therapies for different GBM subgroups may represent a promising new direction for treatment [6] - A concurrent article in Nature Cell Biology discusses the potential origins of GBM heterogeneity from the activation of various gene core regulatory circuits, emphasizing HOXB3's central role in GBM CRC and the therapeutic potential of peptide-mediated targeting [6]

Core Viewpoint - Gene editing technologies, such as CRISPR/Cas9 and next-generation base editing, are powerful tools for correcting pathogenic genes by permanently altering DNA sequences. However, ensuring the avoidance of unintended permanent changes in complex human environments remains a critical focus for broader clinical applications. In this context, epigenetic editing has gained attention as a complementary strategy, allowing precise regulation of gene expression without altering DNA sequences, thus providing new safety perspectives for gene therapy [3][4]. Summary by Sections Epigenetic Editing Potential - Zinc finger proteins and dCas9-based epigenetic editing therapies have shown significant potential, successfully inhibiting PCSK9 expression in mouse and non-human primate models, leading to effective reductions in blood cholesterol levels. PCSK9 is a key protein regulating "bad cholesterol" (LDL-C), making its inhibition an important strategy for cardiovascular disease prevention and treatment [4]. Challenges in Epigenetic Editing - The core challenge of epigenetic editing technology is maintaining long-term stability of the regulatory effects. Epigenetic modifications are dynamically reversible, and artificially established modifications may be diluted or reset during cell division. Current research has limited optimization of editing tools, primarily focusing on DNA methylation mechanisms. Systematic optimization and understanding of the long-lasting molecular mechanisms are essential for advancing this technology from laboratory to clinical applications [4]. Research Breakthroughs - A study published in Nature Biotechnology by teams from the Chinese Academy of Sciences and Anhui Medical University developed optimized epigenetic regulators for durable gene silencing, specifically targeting PCSK9 in non-human primates. The research demonstrated a significantly improved new editing tool with higher delivery efficiency and efficacy compared to existing systems [5][6]. EpiReg-T Development - The research team systematically screened different components and structures of epigenetic editors in mouse models, leading to the development of two superior versions: EpiReg-C based on dCas9 and EpiReg-T based on TALE. EpiReg-T exhibited a strong dose sensitivity, achieving significant suppression of PCSK9 at lower doses, validated in non-human primate models [7][8]. Long-term Efficacy and Safety - EpiReg-T was used for long-term validation, showing stable PCSK9 suppression even after liver cell regeneration. The epigenetic suppression demonstrated a reversible safety feature, allowing restoration of initial expression levels with an activating tool. In non-human primate experiments, a single high dose of EpiReg-T achieved approximately 90% PCSK9 suppression and about 60% reduction in "bad cholesterol," with effects remaining stable over 343 days [10][11]. Molecular Mechanisms - The study revealed that EpiReg-T established two suppressive "marks"—DNA methylation and histone H3K27e3 modification—while significantly downregulating various transcriptional activation modifications. Importantly, no significant off-target effects were observed, confirming the high targeting precision of EpiReg-T even at saturation doses [11][12]. Conclusion - The research successfully developed a highly efficient, durable, and specific epigenetic editor, EpiReg-T, demonstrating "one-time administration, long-term efficacy" in lipid-lowering effects in non-human primates. This study paves the way for the clinical application of epigenetic gene therapy [12].

Core Insights - The article discusses a research paper published in Cell Press that evaluates the global flux of perfluoroalkyl acids (PFAA) from glaciers in the context of climate change, highlighting the urgency for coordinated action in managing historical pollutants and climate mitigation [5][6]. Group 1: Research Findings - The study identifies major PFAA release hotspots, including the Arctic, South Asia, and Central Asia, emphasizing the need for urgent action to manage these pollutants [5][6]. - PFAA, a significant industrial pollutant, poses serious risks to both ecological and human health due to its persistence and accumulation in cold regions, including glaciers [6]. - The research estimates that global glaciers release approximately 3,500 kilograms of PFAA annually, with suspended particles contributing about 12% of this total [6]. Group 2: Implications and Recommendations - The findings fill a critical gap in the global PFAA budget and stress the need for coordinated efforts to manage historical pollutants and mitigate climate change [7]. - The study suggests that controlling PFAA pollution in hotspot areas requires reducing emissions at the source and slowing down glacier melting through climate change mitigation [7]. - Effective strategies to address this dual threat necessitate interdisciplinary collaboration among scientists, local communities, and policymakers [7].

Core Viewpoint - The study highlights the role of ZDHHC11-mediated S-palmitoylation in alleviating chondrocyte senescence and proposes it as a new therapeutic target for osteoarthritis (OA) [2][3][13]. Group 1: Osteoarthritis Overview - Osteoarthritis (OA) is a common degenerative joint disease affecting approximately 595 million people globally, leading to reduced quality of life and significant social costs [2]. - Current treatments include non-steroidal anti-inflammatory drugs, corticosteroids, and joint replacement surgery, but no disease-modifying drugs have been approved for OA [2]. Group 2: Research Findings - The research team developed a lipid nanoparticle (LNP) delivery platform to specifically deliver Zdhhc11 mRNA to chondrocytes, aiming to repair damaged cartilage and alleviate OA progression [3][10]. - ZDHHC11 is highly expressed in joint cartilage cells but downregulated in degenerative cartilage of elderly mice and human OA patients, indicating its potential role in preventing chondrocyte senescence and promoting cartilage synthesis [7][8]. Group 3: Mechanism of Action - The study identifies ZDHHC11 as a key palmitoyltransferase, where its absence exacerbates OA progression in a mouse model, suggesting that ZDHHC11-mediated S-palmitoylation regulates cellular senescence and extracellular matrix metabolism through the GATA4-P65 signaling pathway [8][13]. - S-palmitoylation is a reversible post-translational modification that influences protein function and is implicated in various diseases, including OA [6][7]. Group 4: Future Implications - Targeting ZDHHC11 and its associated pathways may restore joint homeostasis in OA patients, representing a promising new strategy for OA treatment [13].

Core Insights - The study published in Nature Immunology reveals that chemotherapy-induced CA-repeat DNA fragments in breast cancer can trigger antitumor immune responses [3][4]. - The research highlights the relationship between genomic instability and immune regulation, emphasizing the therapeutic potential of CA-rich DNA in enhancing antitumor immunity [7]. Group 1 - The research team demonstrated that in tumors with low expression of MSH2, DNA fragments rich in CA, generated by DNA-damaging chemotherapy, preferentially bind with cGAS, leading to the formation of biomolecular condensates in the cytoplasm and triggering antitumor immune responses [7]. - In contrast, DNA fragments lacking CA released from tumors with high MSH2 expression activate AIM2, resulting in immune suppression through the upregulation of PD-L1 and IDO [7]. - The study found that the increase in CA-rich DNA fragments post-chemotherapy correlates with a rise in tumor antigen-responsive T cells and better chemotherapy responses [7]. Group 2 - The injection of CA-rich DNA fragments into tumors enhances antitumor immunity in PyMT allograft tumors [7]. - Different tumor DNA fragments can elicit opposing immune responses based on their preference for different sensors [7].

Core Insights - The article discusses the release of the "World's Top 2% Scientists" list for 2025, highlighting the impact and achievements of researchers in various fields, particularly in pathology [3][5]. Group 1: Overview of the Ranking - The ranking is a collaboration between Stanford University and Elsevier, focusing on both lifetime scientific influence and annual achievements of researchers [3]. - The data is sourced from Scopus, analyzing over 21.9 million author profiles to select the top 2% of scientists based on citation metrics and H-index [3]. Group 2: Notable Chinese Scientists in Pathology - Five Chinese experts were recognized in the "Lifetime Scientific Influence" category in pathology: Chen Guozhang, Bian Xiuwu, Li Tiejun, Ding Yanqing, and Lai Maode [5]. - Nine Chinese scholars were included in the "Annual Scientific Influence" list for pathology, with notable names such as Chen Guozhang, Bian Xiuwu, and Li Tiejun [5].