撰文丨王聪 编辑丨王多鱼 排版丨水成文 在细胞免疫中，细胞毒性淋巴细胞利用 颗粒酶 A （ Granzyme A， GZMA） 切割并激活成孔蛋白 GSDMB，从而对靶细胞进行焦亡性杀伤。然而，GZMA 是如何识别并切割 GSDMB 的，目前仍不清楚。 2026 年 1 月 26 日，北京生命科学研究院 邵峰 院士团队、中国科学院生物物理研究所 丁璟珒 研究员团 队合作，在 Immunity 期刊 发表了题为： Exosite-mediated targeting of GSDMB by dimeric granzyme A in lymphocyte pyroptotic killing 的研究论文。 该研究表明， 颗粒酶 A （ Granzyme A， GZMA） ，通过独特的"二聚体"结构，像一把精准的钥匙，解 锁了对 GSDMB 蛋白的切割，从而引发"细胞焦亡"。这不仅揭示了淋巴细胞来源的颗粒酶用于杀伤靶细胞 的一种底物靶向机制，还为癌症免疫治疗提供了新思路。 GZMA 的二聚体结构：一把双刃钥匙 在这项新研究中，研究团队通过高精度的晶体结构分析，发现 GZMA 有一个独特之处：它是以"二聚体"形 式 ...

为应对上述挑战，溶瘤病毒的全身给药，已成为改善难以触及的癌症临床疗效的主要研究方向；然而，此 前的研究报告指出，溶瘤病毒全身给药存在一些问题，包括被预先存在的抗病毒中和抗体迅速清除以及潜 在的全身毒性。 尽管提高溶瘤病毒的剂量能够提升其向肿瘤的递送效率，但这也带来了潜在的全身毒性风 险，可能导致严重的副作用甚至患者死亡。 因此，迫切需要开发一种能够增强 溶瘤病毒向肿瘤的递送能力的同时 降低给药剂量的平衡方法。 撰文丨王聪 编辑丨王多鱼 排版丨水成文 溶瘤病毒 （ Oncolytic Viruse， OV） 是癌症治疗中一种很有前景的疗法。这些具有复制能力的病毒既能 感染正常细胞也能感染肿瘤细胞，但它们在肿瘤细胞中选择性复制，从而引发抗肿瘤反应。基于单纯疱疹 病毒 （HSV） 的首个获美国 FDA 批准的溶瘤病毒疗法 Imlygic 瘤内注射治疗黑色素瘤取得了成功，但其 在深部或转移性肿瘤中的治疗效果仍有限。 在这项最新研究中，研究团队开发了基因工程改造的、免疫兼容的细胞膜，其表达 嵌合抗原受体 （CAR） 以被 溶瘤病毒 （OV） ，从而构建了一种肿瘤靶向的溶瘤病毒递送平台—— iNV-GOV ，该平台既能保 ...

Core Viewpoint - The research indicates that Paroxetine, a commonly used antidepressant, shows significant efficacy against malignant melanoma, particularly in cases with BRAF V600E mutations that are resistant to targeted therapies [3][5]. Group 1: Research Findings - A study published in Cell Reports Medicine reveals that Paroxetine induces pyroptosis in melanoma cells, a unique mechanism of cell death distinct from traditional apoptosis [3][7]. - The mechanism involves blocking serotonin reuptake, leading to reduced intracellular serotonin levels, which affects DNA repair gene expression and ultimately results in DNA damage accumulation and endoplasmic reticulum stress [7][9]. - Paroxetine is effective against BRAFi/MEKi resistant melanoma due to lower expression of TPH1, making these cells more sensitive to treatment [11]. Group 2: Clinical Implications - The findings suggest multiple clinical benefits: Paroxetine is an already approved drug with known safety, allowing for quicker clinical application [14]. - It serves dual purposes as both an antidepressant and an anti-cancer agent, making it particularly suitable for advanced cancer patients [14]. - The drug offers new options for patients with resistance to targeted therapies and enhances the effectiveness of immune therapies by transforming "cold tumors" into "hot tumors" [11][14].

Core Viewpoint - Tumor immunotherapy, particularly immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 pathway, shows promise in treating advanced cancers but is limited by insufficient response rates. Recent findings suggest that Gasdermin D-mediated pyroptosis can trigger a robust systemic immune response, with only 15% of pyroptotic tumor cells capable of eliminating the entire tumor, presenting a new strategy for enhancing anti-tumor immunity [2][3][10]. Summary by Sections Research Development - A new self-luminous photodynamic therapy system, CC@PDC, has been developed to efficiently activate pyroptosis and stimulate anti-tumor immunity. This system, when used in conjunction with anti-PD-L1 antibodies, demonstrates superior anti-tumor and immune effects, offering a novel strategy for cancer treatment [3][10]. Mechanism and Composition - The CC@PDC system is designed with efficient resonance energy transfer, effective generation of singlet oxygen (1 O₂), and strong pyroptosis induction capabilities. It consists of amphiphilic porphyrin lipids, camptothecin derivatives, and a targeted assembly that encapsulates oleic acid-modified calcium peroxide and a specific compound to enhance its efficacy in acidic tumor microenvironments [7][10]. Key Findings - The study highlights that the camptothecin-enhanced self-luminous photodynamic chemotherapy can synergistically induce tumor cell pyroptosis and, when combined with anti-PD-L1 antibodies, significantly enhances the anti-tumor immune response, providing a promising new approach for cancer therapy [10][11].

Core Viewpoint - The article discusses the development of a novel peptide, SK56, which selectively blocks the GSDMD-NT pore, thereby delaying pyroptosis and mitigating inflammatory responses, offering new therapeutic options for uncontrolled inflammation-related diseases [3][8][10]. Group 1: Research Findings - The research team utilized artificial intelligence (AI) to generate a specific blocker for the GSDMD-NT pore, which can delay pyroptosis and reduce inflammation, potentially benefiting conditions like sepsis and autoimmune diseases [3][10]. - SK56 effectively targets and blocks the GSDMD-NT pore, preventing cell death induced by inflammatory stimuli and reducing cytokine release from macrophages [8][10]. - The study challenges the traditional belief that pyroptosis is irreversible once triggered, demonstrating that SK56 remains effective even after the pyroptotic response has begun [10][11]. Group 2: Implications and Innovations - The findings highlight the potential of AI-guided peptide design in targeting previously deemed "undruggable" biological structures, paving the way for new biopharmaceutical developments [10]. - The research suggests a paradigm shift in managing inflammation, proposing that humans might coexist with inflammation rather than merely suppressing it [11]. - The AI model and training database used in the study have been made publicly available, promoting further research and development in this area [11].

Core Viewpoint - Tumor immunotherapy, particularly immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 pathway, shows significant promise in treating various advanced cancers, but low immune response rates hinder its efficacy and widespread application [2] Group 1: Research Findings - The study developed a self-luminous nanosystem that enhances the activation of pyroptosis in tumor cells, leading to a strong antitumor immune response when combined with anti-PD-L1 monoclonal antibodies [3][6] - Pyroptosis, a newly discovered form of immunogenic cell death (ICD), releases pro-inflammatory cytokines and damage-associated molecular patterns, triggering a robust antigen-specific immune response [5] - The self-luminous nanoparticles can emit light within the tumor without the need for an external light source, enhancing the generation of reactive oxygen species (ROS) and achieving significant tumor-killing effects [7] Group 2: Mechanism and Components - The nanosystem consists of amphiphilic porphyrin lipids, camptothecin derivatives, and a targeting moiety, which together facilitate the release of oxygen and hydrogen peroxide in the acidic tumor microenvironment [6] - The combination of chemotherapy and self-enhanced photodynamic therapy synergistically activates pyroptosis, driving immune activation that enhances the antitumor response to PD-L1 therapy [7]

Core Viewpoint - The study highlights that high-dose ascorbic acid can selectively induce pyroptosis in LKB1-deficient non-small cell lung cancer (NSCLC) cells and enhance their sensitivity to immune checkpoint inhibitors (ICIs) [4][6]. Group 1: LKB1 Deficiency and Immune Resistance - LKB1 mutations lead to primary resistance to ICIs in NSCLC, characterized by a "cold tumor" subtype with insufficient Tpex cell infiltration [2][6]. - Tpex cells, which are crucial for responding to PD-1/PD-L1 blockade therapies, show high expression levels of the transcription factor TCF1 [2]. Group 2: Mechanism of Action - High-dose ascorbic acid exacerbates oxidative stress in LKB1-deficient NSCLC cells by upregulating the transporter GLUT1, leading to increased accumulation of ascorbic acid [6][8]. - The oxidative stress triggers pyroptosis in LKB1-deficient NSCLC cells through the H₂O₂/ROS-caspase-3-GSDME signaling axis [6][8]. Group 3: Clinical Implications - In preclinical models, high-dose ascorbic acid reverses ICI resistance and reshapes the immune microenvironment characterized by TCF1+ CD8+ T cell infiltration [7][8]. - Pyroptosis-driven immunogenic cell death promotes the maturation of cross-presenting dendritic cells, which is essential for Tpex cell expansion [7][8]. - The study provides a theoretical basis for clinical trials combining ICIs with high-dose ascorbic acid [7][8].

Core Viewpoint - The article highlights the significant contributions of four award-winning scientists from the Beijing Institute of Life Sciences (BILS) to the field of life sciences, emphasizing the institute's unique environment that fosters innovation and original research [1][3][6]. Group 1: Achievements of Award-Winning Scientists - In the past decade, 14 scientists have received the Future Science Prize in the life sciences category, with notable contributions from Shao Feng, Li Wenhui, Zhou Jianmin, and Chai Jijie, all of whom conducted their groundbreaking research at BILS [3][4][5]. - Shao Feng was awarded the Future Science Prize in 2018 for his discovery of receptors and execution proteins involved in the inflammatory response to bacterial endotoxin LPS [3]. - Li Wenhui received the Future Science Prize in 2022 for identifying receptors for hepatitis B and D viruses, aiding in the development of more effective treatments [4]. - In 2023, Chai Jijie and Zhou Jianmin were recognized for their pioneering work on the structure and function of anti-disease bodies in combating plant pests [5]. Group 2: Unique Environment at BILS - BILS, established in 2003, operates without administrative levels or fixed positions, allowing scientists to independently determine their research directions and alleviating funding concerns [6][7]. - The institute's supportive environment encourages scientists to take risks and explore new research areas, as exemplified by Shao Feng's transition from studying bacterial infections to discovering the molecular mechanisms of cell death [12][14]. - Li Wenhui emphasized the importance of a "fact-based" approach at BILS, where open discussions and constructive criticism during weekly meetings foster a culture of rigorous scientific inquiry [23][25]. Group 3: Collaborative Research and Innovation - The collaboration between Chai Jijie and Zhou Jianmin began serendipitously during their time at BILS, leading to significant advancements in understanding plant immunity [31][33]. - Their joint research efforts culminated in the discovery of anti-disease bodies, marking a milestone in the field of plant innate immunity, which was recognized with the Future Science Prize [33][34]. - The institute's culture of collaboration and mutual support among scientists has been pivotal in driving innovative research and achieving notable scientific breakthroughs [36][39].

Core Insights - The Future Science Prize, initiated by Yang Zhenning, celebrates its 10th anniversary in July 2025, recognized as one of the most significant scientific awards in China [2] - Over the past decade, 14 winners in the life sciences have emerged, with notable contributions from researchers at the Beijing Institute of Life Sciences (BILS) [2][3] Group 1: Achievements of Award Winners - Shao Feng received the Future Science Prize in 2018 for discovering receptors and execution proteins involved in the inflammatory response to bacterial endotoxin LPS [2] - Li Wenhui was awarded in 2022 for identifying receptors for hepatitis B and D viruses, aiding in the development of more effective treatments [3][14] - In 2023, Chai Jijie and Zhou Jianmin were recognized for their groundbreaking work on disease-resistant proteins and their structural elucidation [3] Group 2: Environment and Structure of BILS - BILS, established in 2003, operates without administrative levels or fixed positions, allowing scientists to autonomously determine research directions and secure funding [3][4] - The institute has attracted numerous talented young scholars, including Shao Feng, Chai Jijie, Zhou Jianmin, and Li Wenhui, who joined between 2004 and 2007 [3][4] Group 3: Research Philosophy and Collaboration - The culture at BILS emphasizes a "trial and error" approach, encouraging scientists to explore and innovate without the pressure of guaranteed success [10][15] - Regular meetings, such as the PI Club, foster open discussions and critical feedback among researchers, enhancing collaborative efforts and idea generation [17] Group 4: Personal Experiences of Researchers - Shao Feng chose to return to China from Harvard, believing in the potential for significant contributions to modern life sciences [5][6] - Li Wenhui, motivated by personal experiences with hepatitis patients, shifted his focus to hepatitis research upon joining BILS [11][13] - Both researchers attribute their successes to the supportive and flexible environment at BILS, which allows for independent exploration and innovation [8][10][15] Group 5: Impact of BILS on Scientific Community - BILS has played a crucial role in advancing China's scientific landscape through innovative research, talent cultivation, and fostering a collaborative environment [23] - The institute's ability to provide substantial research funding without competitive pressures has attracted top talent and facilitated groundbreaking discoveries [22][25]