Core Viewpoint - The article discusses a novel approach to cancer immunotherapy through the development of an in situ-generated vaccine-like pyroptosome, which activates a strong anti-tumor immune response by inducing pyroptosis in tumor cells, thus providing a new strategy for personalized cancer treatment [3][4][7]. Summary by Sections Research Development - The study introduces a systemic injection of a nano-adjuvant that induces pyroptosis, leading to the secretion of pyroptosomes in the tumor area, which enhances anti-tumor immunity and promotes the elimination of primary tumors and metastatic nodules [3][7]. Mechanism of Action - The mechanism involves several coordinated steps: 1. Induction of pyroptosis: Nano-particles accumulate in the tumor area and induce pyroptosis through specific methods (e.g., light activation), causing cell membrane rupture and release of cellular contents [8]. 2. Formation of pyroptosomes: The released contents, including tumor antigens and pro-inflammatory cytokines, are encapsulated into structures called pyroptosomes, acting as natural in situ vaccines [8]. 3. In situ immune activation: The nano-adjuvant releases TLR7/8 agonists into the pyroptosomes, providing strong immune activation signals, thus forming an efficient in situ vaccine platform that activates all key steps of the cancer-immunity cycle [8]. Advantages and Significance - The technology offers high efficiency and synergy by releasing a large amount of antigens and danger signals, effectively activating both innate and adaptive immunity [9]. - The in situ strategy focuses the immune response locally at the tumor site, avoiding systemic toxicity associated with widespread immune stimulation [9]. - This research represents a sophisticated nanomedicine strategy that safely and effectively manipulates immune responses in the tumor microenvironment, showcasing significant clinical translation potential [11]. Multifunctionality and Prospects - The platform not only clears primary tumors but also inhibits metastatic lesions and provides long-term immune memory to prevent cancer recurrence [13]. - This study provides a new design and conceptual framework for developing more efficient and personalized cancer immunotherapies, such as personalized cancer vaccines [13].

Core Viewpoint - The research reveals the molecular mechanism by which Granzyme A (GZMA) activates Gasdermin B (GSDMB) through a unique dimeric structure, providing insights into lymphocyte pyroptotic killing and potential new avenues for cancer immunotherapy [2][12]. Group 1: Mechanism of Action - GZMA utilizes its dimeric structure to precisely cut and activate GSDMB, leading to pyroptotic cell death, which is crucial for immune responses against infections and tumors [5][12]. - The study identifies that GZMA's dimeric form has two exosites that bind to the C-terminal domain of GSDMB, ensuring accurate cleavage at the Lys244 site, which is essential for GSDMB's activation [7][9]. Group 2: Structural Insights - The dimerization of GZMA is critical for its function, as disrupting this structure impairs its ability to bind and activate GSDMB, while not affecting its ability to cleave other substrates [7][9]. - The precise positioning of the cleavage site at Lys244 is facilitated by the cooperative action of the two GZMA monomers, highlighting the importance of structural integrity for enzymatic function [9]. Group 3: Evolutionary Differences - GSDMB is present in humans but absent in mice, although mouse GZMA can still cleave human GSDMB with reduced efficiency due to differences in key amino acids at the exosite [11]. - The research team engineered a mutant form of mouse GZMA that significantly improved its efficiency in cleaving GSDMB, providing a new tool for studying GZMA-GSDMB pathways in mouse models [11]. Group 4: Implications for Immunotherapy - The findings suggest that enhancing GSDMB-dependent pyroptosis could improve the efficacy of immune cells against tumors, opening new therapeutic strategies in cancer immunotherapy [12]. - The mechanism may also offer new targets for diseases associated with GSDMB, such as asthma and inflammatory bowel disease, indicating broader implications for immune modulation [12].

Core Viewpoint - Oncolytic viruses (OV) represent a promising therapy for cancer treatment, selectively replicating in tumor cells to trigger anti-tumor responses, but systemic delivery remains a challenge due to pre-existing neutralizing antibodies and potential systemic toxicity [3][4]. Group 1 - The research team from Zhejiang University developed a systemically injectable oncolytic virus delivery platform called iNV-GOV, which protects viral particles from immune recognition and directs them to tumor sites, accelerating cancer cell pyroptosis and eliciting a strong anti-tumor immune response [4][5]. - The iNV-GOV platform integrates cancer virotherapy, cell membrane coating technology, CAR targeting, and controlled cell pyroptosis, addressing issues of low viral delivery efficiency and safety while significantly enhancing anti-tumor immune effects [5][7]. Group 2 - The engineered immune-compatible cell membrane expresses chimeric antigen receptors (CAR) to construct the tumor-targeting oncolytic virus delivery platform, functioning as an "invisibility cloak" to protect viral particles and as a "navigation" system to guide them to tumor sites [7]. - The viral load is controlled by a heat shock promoter, allowing ultrasound-induced mild hyperthermia to trigger tumor-specific cell pyroptosis, enhancing tumor lysis and promoting rapid release of oncolytic viruses from lysed tumor cells, thereby increasing infection of adjacent tumor cell populations [7][9]. Group 3 - Overall, this systemically injectable, tumor-targeting oncolytic virus platform enables rapid and sustained proliferation of viruses within tumors, providing a promising new strategy for treating various cancers [9].

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]