Core Insights - A research team led by Han Shuo from the Chinese Academy of Sciences has developed a novel proximity labeling technology that enhances the precision of targeting cancer cells [1][2] - The technology allows scientists to label the "neighbors" of specific molecules, enabling a better understanding of their interactions in the microenvironment [1] - The team aims to transform this observation tool into a therapeutic weapon by engineering a nanoenzyme that significantly improves the efficacy of cancer immunotherapy [1][2] Summary by Sections - **Research Development** - The new proximity labeling technology can increase the targeting effectiveness of cancer immunotherapy by tens to hundreds of times [2] - This method creates a strong artificial target on the surface of cancer cells, which enhances the signaling needed for immune cells to initiate an attack [2] - **Experimental Findings** - In studies involving mouse tumor models and patient samples from breast, gastric, and colorectal cancers, the engineered nanoenzyme demonstrated significant therapeutic effects [1] - The high-density labeling acts as a rallying signal for immune cells, triggering a "strongest attack mode" for precise targeting [2] - **Limitations and Future Directions** - There are limitations to the method, such as difficulties in targeting certain melanoma cells with red light alone [2] - Overall, this research is expected to pave the way for the development of smarter and more efficient next-generation immunotherapies [3]

Group 1 - The article discusses a powerful "molecular mapping technique" known as proximity labeling technology, which allows scientists to catalyze and label the surrounding environment at specific locations within cells, enabling precise identification of specific molecules in the microscopic world [1] - Researchers from the Chinese Academy of Sciences have transformed this technology into a therapeutic tool by developing engineered nanoenzymes responsive to deep red light or ultrasound, successfully creating a powerful "treatment weapon" [1] - In mouse experiments, the team artificially created difficult-to-escape targets on tumors, which not only addresses core challenges in immunotherapy but also stimulates a robust systemic anti-tumor effect [1] Group 2 - The study reveals that in cancer immunotherapy, immune cells require strong and abundant "signals" to initiate attacks, and the natural signals on cancer cells are often sparse [2] - By chemically catalyzing reactions to increase the artificial antigen density on tumor cell surfaces by over 100 times, the researchers significantly enhanced immune recognition efficiency and killing power [2] - The engineered nanoenzymes were instructed to create a strong artificial target on cancer cells, which, when combined with a special bispecific T cell engager, effectively triggered T cells to launch a powerful attack on the targeted area [1][2] Group 3 - After the destruction of cancer cells, more tumor-associated antigens are exposed, which are then captured by antigen-presenting cells and relayed to the immune system, enabling it to autonomously recognize and attack similar cancer cells in the future [2] - The research has shown promising results in both mouse models and clinical tumor samples, paving the way for the development of smarter and more efficient next-generation immunotherapies [2] - In mouse trials, the primary tumor volume was reduced by over 80%, and the immune system activation also suppressed untreated distal tumors, demonstrating long-lasting immune memory against secondary tumor challenges [2]

Core Viewpoint - A research team from the Chinese Academy of Sciences has developed a novel proximity labeling technology that significantly enhances the precision of targeting cancer cells, potentially leading to more effective cancer immunotherapy [1][2]. Group 1: Research Development - The proximity labeling technology allows scientists to accurately identify the "social circle" of specific molecules, effectively tagging their neighbors [1]. - The research team has engineered a nanoenzyme to transform this labeling technology into a therapeutic tool, demonstrating significant efficacy in mouse tumor models and patient samples related to breast, gastric, and colorectal cancers [1]. Group 2: Treatment Mechanism - In cancer immunotherapy, this method can enhance the effectiveness of immune cell attacks by tens to hundreds of times, addressing the challenge of sparse natural signals on cancer cell surfaces [2]. - The engineered nanoenzyme can create a strong artificial target on cancer cells using red light or ultrasound, triggering a powerful attack mode for precise targeting [2]. Group 3: Future Implications - This research is expected to pave the way for the development of smarter and more efficient next-generation immunotherapies [3].

Core Viewpoint - The research identifies CD160⁺ CD8⁺ T cells as a key factor in enhancing the efficacy of anti-PD-1 immunotherapy in colorectal cancer by regulating T cell exhaustion and overcoming resistance [2][5][7]. Group 1: Research Findings - The study found that CD160⁺ CD8⁺ T cells are specifically enriched in the ileum and possess unique characteristics, including resistance to terminal exhaustion and strong clonal expansion [5]. - CD160⁺ CD8⁺ T cells significantly inhibited tumor growth in colorectal cancer models with high microsatellite instability and inflammation [5]. - CD160 gene knockout accelerated tumor growth, while the transfer of CD160⁺ CD8⁺ T cells alleviated this effect, indicating their potential therapeutic role [5]. Group 2: Mechanism of Action - The research revealed that CD160 interacts with PI3K (p85α) and promotes the expression of FcεR1γ and 4-1BB through the AKT-NF-κB pathway, enhancing the cytotoxicity of CD8⁺ T cells [5][7]. Group 3: Therapeutic Implications - The study proposes an innovative immunotherapy strategy involving the infusion of CD160⁺ CD8⁺ T cells to overcome anti-PD-1 resistance, presenting advantages over existing therapies like TIL and CAR-T [7]. - A prospective, open-label interventional clinical trial has been initiated to explore the safety and preliminary efficacy of CD160⁺ CD8⁺ T cells combined with anti-PD-1 monoclonal antibodies in treating colorectal cancer [7]. Group 4: Commentary - A commentary published in Nature Cell Biology highlights the potential of CD160⁺ CD8⁺ T cells in regulating anti-tumor immune responses and improving treatment outcomes when combined with immune checkpoint blockade [8].

Core Viewpoint - The research highlights the potential of targeting necrotic lipid release in tumors to enhance immunosurveillance and improve cancer immunotherapy for glioblastoma, providing new therapeutic targets for this deadly brain tumor [2][5]. Group 1: Research Findings - The study utilized non-cancerous mouse embryonic stem cells to construct a genetically identical mouse teratoma model and identified genes affecting early cancer immune editing through whole-genome CRISPR screening [5]. - The deletion of pro-apoptotic tumor suppressor genes, including Trp53, exacerbated cell necrosis within teratomas, leading to the release of APOE lipid particles into the extracellular environment [5]. - Infiltrating T cells attracted to necrotic tumor regions accumulated lipids and became dysfunctional, but blocking T cell lipid uptake or inactivating mitochondrial permeability transition pore (mPTP) could reduce cell necrosis and restore immune surveillance [5]. Group 2: Implications for Human Cancer - The research further investigated the interaction between tumors and immunity in human glioblastoma (GBM), revealing that infiltrating T cells in TP53 mutant human GBM also exhibited APOE accumulation and dysfunction [5]. - The combination of anti-APOE antibodies with anti-PD-1 antibodies was found to synergistically enhance anti-tumor immune responses and prolong survival in mouse models [5]. Group 3: Mechanistic Insights - The study elucidated the association between mPTP-mediated tumor necrosis and immune evasion, indicating that inhibiting the uptake of lipids released from necrotic tumor cells by infiltrating immune cells can enhance the efficacy of cancer immunotherapy [5].

记者 黄海华 贝尔托齐是美国国家医学院、美国国家科学院、美国国家发明家科学院以及美国艺术与科学院四院 院士。她的团队不仅发明了用于免疫肿瘤治疗的靶向酶疗法，还开发了用于疾病生物标志物发现的糖蛋 白组学技术、用于结核病的即时诊断方法，以及用于诊断早发型糖尿病和病毒感染的超灵敏抗体检测技 术。 昨天，"浦江科学大师讲坛"第十二期在复旦大学相辉堂开讲。美国斯坦福大学教授、2022年诺贝尔 化学奖得主、2024年美国化学会最高荣誉普利斯特里奖章得主卡罗琳·露丝·贝尔托齐，作题为《甜蜜的 复仇：癌症免疫治疗中的"去糖"行动》的主旨报告。 市政协副主席吴信宝出席讲坛并向贝尔托齐颁发主讲人证书。 ...

Core Viewpoint - HCW Biologics (HCWB.US) experienced a nearly 70% surge in stock price, reaching $5.81, following the announcement of a second-generation immunotherapy drug based on Pembrolizumab targeting solid tumors, particularly pancreatic and ovarian cancers [1] Company Summary - HCW Biologics has developed a novel proprietary TRBC product discovery and development platform technology for its new immunotherapy drug [1] - The company highlighted that immune checkpoint inhibitors (ICIs), introduced in cancer treatment since 2011, are considered groundbreaking therapies but have shown a lack of immune cell co-stimulation activity, which diminishes their anti-tumor efficacy [1]

Group 1 - HCW Biologics experienced a nearly 70% surge in stock price, reaching $5.81, following the announcement of a second-generation immunotherapy drug based on Pembrolizumab targeting solid tumors, particularly pancreatic and ovarian cancers [1] - The company utilizes a novel proprietary TRBC product discovery and development platform technology for its new drug [1] - Since the introduction of immune checkpoint inhibitors (ICIs) in cancer treatment in 2011, they have been recognized as breakthrough therapies, although the company noted that preclinical and clinical studies indicate ICIs lack co-stimulatory activity of immune cells, reducing their anti-tumor efficacy [1]

Core Viewpoint - HCW Biologics (HCWB.US) experienced a nearly 70% surge in stock price, reaching $5.81, following the announcement of a second-generation immunotherapy drug based on pembrolizumab targeting solid tumors, particularly pancreatic and ovarian cancers [1] Company Summary - The company has developed a novel proprietary TRBC product discovery and development platform technology for its new immunotherapy drug [1] - Since the introduction of immune checkpoint inhibitors (ICIs) in cancer treatment in 2011, they have been recognized as breakthrough therapies [1] - The company highlighted that preclinical and clinical studies indicate that ICIs lack co-stimulatory activity of immune cells, which diminishes their anti-tumor efficacy [1]

Core Viewpoint - The study highlights the role of lactic acid in creating an immunosuppressive tumor microenvironment by activating the MondoA-TXNIP pathway, which inhibits CD8⁺ T cell responses and enhances T reg cell function, thereby promoting tumor growth and immune evasion [2][3][6]. Group 1 - Lactic acid accumulation in the tumor microenvironment damages CD8⁺ T cell cytotoxicity and promotes the immunosuppressive function of T reg cells, establishing a dual immune suppression barrier [2]. - The research team discovered that targeting the MondoA-TXNIP signaling axis can restore anti-tumor immunity in lactic acid-induced immunosuppressive environments and enhance the efficacy of anti-PD-1 therapy [3][7]. Group 2 - The study reveals that the transcription factor MondoA induces TXNIP, which is a common feature in the response of T reg and CD8⁺ T cells to lactic acid [6]. - MondoA deficiency in T reg cells reduces their immunosuppressive capacity, while its absence in lactic acid-induced environments enhances CD8⁺ T cell cytotoxicity by restoring glucose uptake and glycolysis [6]. Group 3 - Targeting the MondoA-TXNIP signaling axis can enhance anti-tumor immunity across various cancer types and synergize with anti-PD-1 therapies, particularly promoting effective T cell responses in colorectal cancer [7][10]. - The combination of MondoA inhibitor SBI-477 with anti-PD-1 monoclonal antibodies produces a synergistic anti-tumor effect, and SBI-477 alone is effective against microsatellite stable (MSS) tumors, which typically show poor T cell infiltration and resistance to immune checkpoint inhibitors [7][10].