编译丨王聪 编辑丨王多鱼 排版丨水成文 T 细胞耗竭 （ T cell exhaustion ） 是慢性感染和肿瘤微环境中普遍存在的现象，严重削弱了抗肿瘤和抗病毒免疫的有效性。 近年来，在理解 T 细胞耗竭的潜在机制方面取得了重大进展，包括导致这种功能障碍状态的外部因素和细胞内在变化。诸如持续的抗原暴露、免疫检查点信号转 导和细胞因子环境等关键外部因素，以及代谢过程改变、表观遗传修饰和转录重编程等内在变化，均会导致 T 细胞功能障碍。 靶向 T 细胞耗竭的新兴疗法旨在恢复免疫功能，并增强抗肿瘤和抗病毒免疫力。这些治疗策略包括免疫检查点抑制、细胞因子疗法、代谢重编程以及细胞疗法。 尽管取得了这些进展，但逆转 T 细胞耗竭仍面临诸多挑战 （例如患者的个体差异、耐药性以及潜在的副作用） 。此外，准确评估 T 细胞功能恢复的标志物以及 这些治疗方法的长期影响，仍是具有挑战性的研究领域。 2026 年 1 月 1 日，苏州大学苏州医学院 周芳芳 教授、浙江大学生命科学研究院 张龙 教 授 、 绍兴市上虞人民医院 虞伟星 医生等， 在 Signal Transduction and Targeted Therapy 期刊 ...

Core Viewpoint - The research published by the University of Pennsylvania reveals that the strong immune response triggered by mRNA vaccines is a result of the synergistic interaction between two core components: modified mRNA and lipid nanoparticles (LNP), which together guide the immune system to produce effective germinal center responses, leading to the generation of durable neutralizing antibodies and memory B cells [1][2][18]. Group 1: Mechanism of mRNA Vaccines - mRNA vaccines deliver mRNA encoding viral proteins to human cells, prompting them to produce viral antigens and train the immune system. Early studies indicated that unmodified mRNA could cause excessive inflammatory responses, which scientists mitigated through nucleotide modifications [5][6]. - The study challenges the traditional view that modified mRNA is "immune-silent," demonstrating that mRNA components can induce the production of type I interferons (IFN-α and IFN-β), which activate dendritic cells (DC) and enhance the differentiation of follicular helper T (Tfh) cells, crucial for germinal center responses [8][9]. Group 2: Role of Lipid Nanoparticles (LNP) - LNPs, typically seen as mere carriers for mRNA, possess significant adjuvant activity, directly regulating the transcriptional program of dendritic cells and promoting Tfh cell differentiation [10][11]. - LNPs induce dendritic cells to express soluble CD25, which neutralizes IL-2, a cytokine that inhibits Tfh cell differentiation, thereby facilitating Tfh cell development [11]. - The study shows that LNPs enhance immune signaling locally at the injection site, explaining their high efficiency and safety [11][12]. Group 3: Synergistic Effects of mRNA and LNP - The research indicates that both mRNA and LNP components are essential for optimal immune responses. Using LNP alone with recombinant proteins resulted in weaker immune reactions compared to the combination with modified mRNA [13][14]. - The presence of mRNA enhances the quality of Tfh cells, making them more likely to produce IFN-γ and IL-21, which are critical for B cell responses, ultimately leading to stronger neutralizing antibody titers [13][14]. Group 4: Implications for Future Vaccine Design - This study not only elucidates the mechanisms behind the success of mRNA vaccines but also provides a blueprint for the design of next-generation vaccines. Adjustments to mRNA modifications or LNP components could precisely regulate the type and intensity of immune responses [16][18]. - The principles derived from this research could extend to cancer vaccines or infectious disease vaccines, enabling more effective immunotherapies [16].

Summary of GRI Bio Conference Call Company Overview - GRI Bio is a clinical-stage biotech company focused on developing NKT cell modulators for treating inflammatory, fibrotic, and autoimmune diseases [2][20] - The company has a focused pipeline with its lead program GRI-0621 currently in a Phase 2A study for idiopathic pulmonary fibrosis (IPF) [2][20] Key Programs and Clinical Studies - GRI-0621 is in a Phase 2A study for IPF, with top-line data expected later this month [2][7] - A second asset, GRI-0803, is focused on systemic lupus erythematosus and is expected to enter clinical studies next year [3][19] - GRI Bio has a pipeline of approximately 500 proprietary compounds for future development [3] Mechanism of Action - GRI Bio's technology aims to regulate the adaptive and innate immune systems, particularly through the modulation of NKT cells [3][4] - NKT cells play a crucial role in mediating crosstalk between the adaptive and innate immune systems, which is significant in diseases like IPF [4] Clinical Data and Efficacy - Preliminary data from GRI-0621 shows positive interim results after two and six weeks of therapy [7][12] - The drug has demonstrated significant reductions in fibrosis in various animal models compared to nintedanib, a current treatment for IPF [9][10] - GRI-0621 is a once-a-day oral formulation with extensive safety data from over 1,700 patients [11][12] Market Opportunity - IPF is a rare, chronic disease with a median survival of 2-3 years and a high unmet need for effective therapies [11] - Current approved drugs for IPF generate approximately $4 billion annually but do not significantly improve mortality outcomes [11] Biomarker Analysis - The Phase 2 study includes extensive biomarker analysis to assess collagen formation and degradation, which are critical in understanding fibrosis [13][15] - Changes in collagen types indicate potential for inducing lung repair mechanisms, which is vital for IPF patients [16] Competitive Landscape - The company differentiates itself by targeting core biological mechanisms driving chronic inflammatory and fibrotic diseases [18] - There is a high unmet need in the lupus treatment space, with only two drugs approved in the last 50 years [19] Conclusion - GRI Bio is positioned to create significant value for shareholders and improve treatment options for patients with chronic diseases [20]

Core Viewpoint - The research highlights the immune-regulating properties of Zeaxanthin, a nutrient found in leafy vegetables and corn, which enhances CD8+ T cell function and improves anti-tumor immunity, indicating its potential as a dietary supplement in cancer therapy [3][10]. Group 1: Research Findings - Zeaxanthin is identified as an immune modulator that enhances the function of CD8+ effector T cells, thereby increasing anti-tumor immunity [3][10]. - Oral supplementation of Zeaxanthin improves the efficacy of anti-PD-1 immune checkpoint inhibitors and enhances the cytotoxicity of TCR-engineered CD8+ T cells against tumor cells [9][10]. - The study utilized a "blood nutrient" library to identify dietary nutrients that influence CD8+ T cell function, revealing that trans-18:1 fatty acid (TVA) also promotes CD8+ T cell activity and response to immunotherapy [6][8]. Group 2: Mechanisms of Action - Zeaxanthin enhances T cell receptor (TCR) signaling on CD8+ T cells, improving their functional response [9][10]. - The research indicates that the structural isomer Lutein does not exhibit the same immune-enhancing effects as Zeaxanthin, underscoring the unique properties of Zeaxanthin [8][10]. - The findings suggest that dietary components can play a significant role in modulating immune responses, particularly in the context of cancer treatment [5][12].

Core Viewpoint - Shanghai Fosun Pharmaceutical Group Co., Ltd. announced a licensing agreement with Sitala for the global development, production, and commercialization of FXS6837, excluding China and its regions [1][6] Licensing Product Information - FXS6837 is a small molecule inhibitor developed by Fosun Pharmaceutical, aimed at treating immune modulation-related diseases, currently in Phase II clinical trials in China [2] - As of July 2025, Fosun has invested approximately RMB 120 million (around $17 million) in the development of FXS6837 [2] - The global sales for major drugs treating related diseases are projected to reach approximately $3.8 billion in 2024 [2] Counterparty Information - Sitala, founded in May 2021 and based in the UK, focuses on developing innovative drugs for inflammatory and autoimmune diseases [3] - The company is backed by several well-known investment institutions from Europe and the US, although specific financial data is confidential due to its non-public status [3] Licensing Agreement Details - The agreement grants Sitala exclusive rights to develop, produce, and commercialize the licensed product globally, excluding China [6] - Sitala will pay up to $19 million in non-refundable upfront payments, including a $2.5 million upfront fee and up to $16.5 million in development and commercialization milestone payments [6] - Additionally, Sitala is obligated to pay up to $48 million in sales milestone payments based on annual net sales in the licensed region [6] - The agreement is effective as of August 26, 2025, and is governed by New York State law [6]

Group 1 - Heptagon Pharma announced the latest progress in its core patent rights protection, with the National Intellectual Property Administration maintaining the validity of its "combination molecule" patent, which involves the use of transgenic animals to produce fully human heavy chain antibodies (HCAb) [1] - The "combination molecule" patent is central to Heptagon Pharma's Harbour Mice® platform, which has established collaborations with several well-known pharmaceutical companies globally, indicating significant commercial value [1] Group 2 - Yunnan Baiyao's JZ-14 capsule, a first-in-class small molecule immunomodulator developed by its subsidiary, has received clinical trial approval, showing significant immunomodulatory and anti-proliferative activity in ulcerative colitis and various tumor models [2] - Successful clinical translation of JZ-14 could fill a gap in the immunomodulation field and expand Yunnan Baiyao's presence in chemical drug innovation [2] Group 3 - Rongchang Bio's product, Taihetai (RC18), has received orphan drug designation from the European Commission for the treatment of myasthenia gravis, which provides various policy supports including scientific advice on development plans and a ten-year market exclusivity post-approval [3] Group 4 - Merck's Clesrovimab (MK-1654) injection application is proposed for priority review by the National Medical Products Administration, aimed at preventing lower respiratory tract infections caused by RSV in newborns and infants entering or born during the RSV season [4] - Clesrovimab's long-acting protective characteristics may alter the current RSV prevention landscape, necessitating attention to its competitive differentiation from vaccines and pricing strategies [4]

Core Viewpoint - The study reveals that Itaconate, contrary to its traditional anti-inflammatory perception, promotes inflammatory responses in tissue-resident alveolar macrophages, exacerbating acute lung injury [2][9]. Group 1: Effects of Itaconate - Itaconate enhances the production of pro-inflammatory cytokines and activates the NLRP3 inflammasome in alveolar macrophages [4][7]. - Pre-treatment with Itaconate worsens LPS-induced lung tissue damage, while knocking out ACOD1 significantly improves survival rates in acute lung injury mouse models [2][6]. Group 2: Comparison with Bone Marrow-Derived Macrophages - The response of bone marrow-derived macrophages (BMDM) to Itaconate is opposite to that of tissue-resident alveolar macrophages, indicating the critical role of the pulmonary microenvironment in shaping macrophage immune metabolism [5][10]. Group 3: Itaconate Derivatives - Unlike natural Itaconate, its derivatives, dimethyl itaconate (DI) and 4-octyl itaconate (4OI), can inhibit the inflammatory response in alveolar macrophages [4][7]. Group 4: Implications for Clinical Treatment - The findings suggest that further research is necessary before considering Itaconate for clinical applications in treating inflammatory diseases, given its unexpected pro-inflammatory role in tissue-resident alveolar macrophages [9][10].

Core Insights - The health industry is experiencing significant growth, with products derived from sika deer gaining popularity due to their unique nutritional and medicinal values [1] - The establishment of Zunxi Deer Biotechnology Research Institute (Hubei) focuses on comprehensive research of sika deer products, particularly in quality testing and component analysis, laying a solid foundation for the healthy development of the sika deer industry [1] Component Analysis - Sika deer products contain complex components beneficial to human health, prompting the formation of a specialized research team at Zunxi Deer Biotechnology Research Institute, comprising experts from biochemistry, pharmacy, and nutrition [2] - Research on deer antler revealed that every 100 grams contains 50-60 grams of amino acids, including all eight essential amino acids, and 10-15 grams of peptides with varying biological activities [2] - The presence of "uridine" in deer antler shows significant effects in animal experiments, enhancing stem cell vitality and improving aging indicators when administered at a dosage of 50 mg per kg body weight [2] Blood Component Analysis - Advanced blood component analysis techniques were employed to study deer blood, revealing that immunoglobulin levels are 2-3 times higher than in ordinary animal blood, indicating strong immune-regulating properties [3] - The optimal conditions for superoxide dismutase (SOD) activity in deer blood were found to be at pH 7.0-7.5 and 37°C, effectively clearing free radicals and reducing oxidative stress [3] - The synergistic effect of hemoglobin and other active components in deer blood enhances nutrient absorption and utilization in the human body [3] Industry Advancement - The research outcomes from Zunxi Deer Biotechnology Research Institute are being transformed into practical applications, driving the upgrade of the sika deer industry [4] - New products have been developed based on the understanding of sika deer product components, such as deer antler essence skincare products and deer blood products combined with other health ingredients to meet diverse consumer health needs [4] - The institute's research supports the establishment of standardized quality and testing methods for sika deer products, promoting market order and healthy development of the industry [4] - Continuous exploration and practice in component analysis inject innovation into the sika deer industry, enhancing product quality and market competitiveness [4]

Core Insights - Allergic rhinitis combined with adenoid hypertrophy in children is a growing concern, affecting respiratory quality and potentially leading to various developmental issues [1][2] - The product Jing Sheng Peptide Oral Solution is gaining attention for its dual immune regulation mechanism, which significantly alleviates symptoms and interrupts the disease's vicious cycle [1][3] Group 1: Disease Overview - Allergic rhinitis is one of the most common diseases in children, with a rising global incidence [2] - The adenoid, located in the nasopharynx, can become pathologically enlarged due to allergic reactions, leading to nasal obstruction and symptoms such as nasal congestion, runny nose, snoring, and mouth breathing [2] - The interplay between allergic rhinitis and adenoid hypertrophy can create a vicious cycle, worsening symptoms and impacting children's quality of life, growth, and mental health [2] Group 2: Treatment Mechanism - Traditional treatments for allergic rhinitis and adenoid hypertrophy have limitations, making immune therapy a promising alternative [3] - Jing Sheng Peptide Oral Solution enhances T lymphocyte activity, promotes the secretion of cytokines like IL-2 and gamma-interferon, and activates macrophages, improving various immunoglobulin levels [3] - The solution also helps to rebalance Th1/Th2 immune responses by inhibiting the secretion of IL-4 and IL-5, thus reducing allergic reactions in children [3] Group 3: Clinical Evidence - Multiple studies, including a randomized controlled trial led by Professor Xu Zhengmin from Fudan University, have validated the efficacy and safety of Jing Sheng Peptide Oral Solution [4] - After 8 weeks of treatment, children showed significant reductions in adenoid size and improvements in symptoms such as mouth breathing, sleep disturbances, nasal congestion, and sneezing [4] - The safety profile of the solution is robust, with no abnormal safety indicators reported in clinical studies, attributed to its formulation from healthy bovine spleen without hormones or dependency issues [4] Group 4: Future Outlook - The ongoing development in the field of immune regulation is expected to benefit more children, promoting healthier growth [5] - There is a call for increased awareness among parents and society regarding children's immune health to create a better environment for their development [5]