转自：中国科学报 2025年，免疫学研究在基础、转化乃至临床等方面均取得了显著进展，尤其在生物机械力免疫、免疫代 谢、神经免疫以及免疫衰老等方向有重大突破。本文总结了2025年免疫学领域的最新研究成果。 一、生物力免疫 纪念斯隆·凯特琳癌症中心Richard M. White教授实验室发现黑色素瘤细胞在受到微环境机械挤压时，会 迅速形成"护核笼"，进而通过重塑染色质，激活相关转录程序，推动细胞从增殖状态切换到侵袭态。该 研究明确了外力作为调控肿瘤细胞命运和耐药的重要环境信号，为理解肿瘤进展及开发干预癌细胞可塑 性提供了新视角。 二、免疫代谢 2025年，生物机械力与免疫研究持续升温。越来越多的研究表明，免疫细胞不仅能感知化学信号，还能 将拉伸、压缩、剪切等机械刺激转化为精细的免疫调控信息。 我们团队首次利用生物力学信号成功解偶联CAR-T细胞的增殖与分化程序，建立了高效制备干性CAR-T 细胞的完整技术，仅4.5天即可制备出应用级的干性CAR-T细胞，针对多种实体肿瘤表现出更强的肿瘤 浸润和持久抗肿瘤效应。这项研究为突破实体瘤CAR-T治疗瓶颈提供了全新理论框架和可转化路径。 美国西奈山伊坎医学院胡宏镇教授团 ...

Core Viewpoint - The article discusses the advancements in anti-aging research, highlighting a shift from basic science to clinical applications, with significant breakthroughs expected by 2025 that could lead to interventions in the aging process and extended healthspan [1]. Group 1: Breakthroughs in Anti-Aging Research - The research from Washington University reveals the role of meningeal lymphatics in regulating synaptic physiology, showing that restoring lymphatic function in aged mice can reverse memory deficits [3][4]. - A study published in Nature identifies the loss of the Y chromosome as a potential new target in anti-aging and cancer research, linking it to cancer progression and immune response deterioration in males [6]. - Research from the Chinese Academy of Sciences demonstrates that the metabolite betaine can mimic exercise effects, providing a new strategy for systemic anti-aging interventions [10]. Group 2: Mechanisms of Aging and Longevity - A study from Harvard Medical School indicates that lithium deficiency is linked to cognitive decline and Alzheimer's disease, with lithium supplementation reversing memory loss in mice [13]. - Research from Altos Labs introduces the concept of "mesenchymal drift," where cells lose their identity with age, and suggests that partial reprogramming can reverse this process [16]. - A study from Baylor College of Medicine reveals how lysosomal changes in parents can promote longevity in offspring through epigenetic mechanisms [19]. Group 3: DNA Repair and Aging - Research from Tongji University highlights a mutation in the cGAS protein in naked mole-rats that enhances DNA repair and extends lifespan, suggesting new strategies for human longevity [21]. - A study on bowhead whales identifies a cold-inducible protein that aids in DNA repair, contributing to their long lifespan and low cancer risk [24][26]. Group 4: Dietary and Reproductive Factors in Longevity - Research from Westlake University shows that protein restriction can reprogram the proteomic landscape in aging mice, offering insights into dietary interventions for longevity [28]. - A large-scale study from Otago University finds that sterilization and contraception can significantly extend lifespan across vertebrates, suggesting that energy allocation away from reproduction may enhance longevity [31][32]. Group 5: Immunity and Aging - A study from Zhang Feng's team demonstrates that mRNA technology can temporarily enhance liver function to produce immune factors, reversing immune aging in mice and improving responses to vaccines and cancer treatments [36].

Core Viewpoint - The article presents a new framework centered on the thymus in understanding immune aging, highlighting its critical role in the decline of immune function and exploring potential intervention strategies [1][4]. Group 1: Thymus and Immune Aging - Immunosenescence is characterized by increased disease susceptibility, reduced vaccine efficacy, and chronic low-grade inflammation, which diminishes the effectiveness of cancer immunotherapy [1][4]. - The thymus is identified as a key organ in the immune system, responsible for training T cells, and its decline is noted to begin as early as puberty, leading to significant reductions in naive T cell numbers and diversity [4][8]. - Unlike other immune organs, thymic atrophy is largely irreversible, making it a critical failure point in the immune axis and a prime target for interventions against immune aging [12][15]. Group 2: Factors Influencing Thymic Decline - Thymic decline is influenced by several factors, including hormonal changes during puberty, infection burden, oxidative stress, and regulation of the FOXN1 gene, which is crucial for thymic epithelial cell function [14][15]. - Clinical observations indicate that individuals who undergo thymectomy experience long-term immune deficiencies, underscoring the thymus's importance in maintaining immune health [8][12]. Group 3: Implications for Future Research - The article emphasizes that protecting thymic function may be essential for long-term immune health, suggesting that strategies to avoid unnecessary infections, reduce chronic inflammation, and maintain hormonal balance could help delay thymic decline [17]. - Targeting thymic regeneration could not only improve the quality of life for the elderly but also lead to breakthroughs in cancer immunotherapy and vaccine development [17][15].

Core Viewpoint - The article discusses a breakthrough in reversing immune aging through mRNA technology, which allows the liver to temporarily act as a "protein factory" to produce three key immune nutritional factors, enhancing immune responses in aged mice [1][2]. Group 1: Immune Aging and Its Challenges - Aging leads to significant changes in the immune system, including thymic shrinkage and reduced T cell production, resulting in decreased immune diversity and response to pathogens and cancer [4]. - Traditional methods to reverse immune aging, such as hormone therapy and cytokine injections, have shown limited effectiveness and often come with side effects [5][6]. Group 2: Innovative Approach - The research team utilized multi-omics analysis to identify weakened immune signaling pathways in aged mice, specifically the Notch, FLT3L, and IL-7 pathways, which are crucial for T cell development and function [8]. - A liver DFI reconstruction strategy was designed, encapsulating mRNA coding for DLL1, FLT3L, and IL-7 in lipid nanoparticles (LNP) for intravenous injection targeting the liver, which retains good function even in old age [8]. Group 3: Remarkable Outcomes - Post-treatment, aged mice exhibited significant thymic regeneration, increased new T cell numbers, and improved T cell receptor diversity, indicating a rejuvenation of the immune system [11]. - The treated aged mice showed a twofold increase in antigen-specific T cell numbers and response intensity to vaccines, nearing levels seen in younger mice [12]. - In tumor models, 40% of treated aged mice completely cleared tumors, while all control mice died due to tumor progression, indicating enhanced anti-tumor capabilities [14]. Group 4: Safety and Reversibility - The therapy is characterized by its safety, as effects diminish after treatment cessation, avoiding long-term uncontrolled risks. In models prone to spontaneous diabetes, the treatment did not accelerate disease progression, indicating it does not disrupt immune tolerance [18]. - Compared to traditional recombinant cytokine therapies, the mRNA approach resulted in significantly reduced systemic inflammatory responses and maintained normal liver and kidney function indicators, showcasing better safety profiles [19]. Group 5: Future Prospects - This research highlights the potential of using the liver for therapeutic protein production, which could serve as a universal strategy against age-related diseases, including cancer [21]. - The method's adjustability and reversibility allow for precise control over treatment duration, and it may be applicable to other key factors diminished by aging, offering new insights for various age-related diseases [21][22]. - The study opens new paradigms for systemic treatment through organ-specific delivery, providing innovative solutions to combat immune aging [23].

Core Viewpoint - The article discusses the relationship between aging and the immune system, emphasizing how immune responses change with age and the potential for manipulating immune function to extend healthy lifespan [2][24]. Group 1: Aging and Immune Response - Aging leads to significant changes in immune cell function, including a bias towards myeloid output from bone marrow, accumulation of senescent T cells, and increased levels of systemic inflammatory cytokines [6][24]. - The immune system is increasingly recognized as a key regulator of systemic aging, potentially driving the aging process rather than merely responding to it [24]. Group 2: Mitochondrial Function and Immune Aging - Mitochondrial dysfunction is central to immune aging, as age-related decline in mitochondrial function weakens immune responses and promotes chronic inflammation [7][8]. - Mitochondria also play a role in systemic signaling, influencing immune responses across different tissues, which is often overlooked in current models of immune aging [7][8]. Group 3: Spaceflight as a Model for Aging - Research using spaceflight environments reveals that many immune changes observed in aging, such as increased inflammatory mediators and impaired adaptive immune responses, can also occur in microgravity [9][12]. - This suggests that spaceflight can serve as a valuable model for studying the mechanisms of immune aging [9][12]. Group 4: Vaccine Response in the Elderly - Elderly individuals typically exhibit lower antibody titers and fewer memory B cells post-vaccination, leading to impaired protective immune responses [14]. - Recent findings indicate that the germinal center response in older adults can be enhanced, paving the way for improved vaccine strategies tailored to aging populations [14]. Group 5: T Cell Changes with Age - Aging is associated with various changes in T cells, including reduced diversity in T cell receptor repertoires and a shift towards inflammatory phenotypes [15][16]. - Understanding whether these changes are adaptive or degenerative is crucial for developing therapeutic strategies targeting age-related immune dysfunction [15][16]. Group 6: Personalized Immunotherapy - The potential of immune modulation in treating diseases is significant, with a focus on how aging affects the efficacy of immunotherapies like CAR-T cell therapy [19]. - Tailoring immunotherapy strategies based on age-related changes in immune cell function could enhance treatment outcomes across different age groups [19]. Group 7: Future Directions in Aging Research - The field must transition from defining aging processes to developing interventions, including identifying biomarkers and strategies to selectively target pathological aging cells [21]. - Integrating artificial intelligence with systems immunology could provide new insights into the regulatory nodes of immune aging, potentially allowing for interventions that recalibrate immune responses to slow aging [24][21].

Core Viewpoint - Urolithin A (UA) is a compound produced from foods rich in ellagitannins, such as pomegranates and raspberries, that activates mitophagy and improves mitochondrial health, showing potential in combating age-related immune decline and inflammation [3][4][7]. Group 1: Research Findings - A study published in Immunity demonstrated that UA can promote the expansion of T memory stem cells (Tscm), providing a rejuvenated immune system that can suppress cancer growth [3]. - A randomized, double-blind, placebo-controlled trial indicated that short-term oral administration of UA (1000 mg daily for 4 weeks) can regulate the composition and function of immune cells, supporting its potential against age-related immune decline [4][7]. - The trial involved 50 healthy middle-aged participants, with results showing that UA increased peripheral initial CD8+ T cells and improved their fatty acid oxidation capacity by 14.72 percentage points [7][8]. Group 2: Immune Cell Changes - UA treatment resulted in changes to the phenotype of CD8+ T cells, indicating a metabolic reprogramming of human immune cells [9][10]. - Enhanced mitochondrial biogenesis and an increase in peripheral blood CD56dim CD16bright NK cells were observed, along with improved TNF secretion and monocyte phagocytosis [11]. - Exploratory single-cell RNA sequencing revealed that UA drives transcriptional changes in immune cell populations, regulating pathways related to inflammation and metabolism [11][12]. Group 3: Overall Implications - Overall, the findings suggest that short-term supplementation of UA can modulate the composition and function of human immune cells, supporting its potential to counteract age-related immune decline and inflammatory aging [13].

Core Insights - The article discusses the advancements in cancer immunotherapy and highlights the challenge of low response rates, with less than 20% of cancer patients achieving durable responses to immunotherapy [2] - It emphasizes the role of immune senescence in tumor microenvironments as a key factor leading to resistance to immunotherapy, suggesting that targeting immune aging could enhance treatment efficacy [3][9] Group 1: Research Findings - A recent study published in Nature Medicine confirmed that immune senescence in the tumor microenvironment is a critical factor for immunotherapy resistance, demonstrating that senolytic drugs combined with anti-PD-1 therapy significantly improved response rates in head and neck squamous cell carcinoma (HNSCC) patients [3][6] - The study involved a Phase 2 clinical trial with 51 patients, revealing that treatment-related adverse reactions were associated with decreased levels of CCR7+ CD4+ naive T cells and CD27+ memory B cells, alongside high expression of immune senescence-related genes [6][7] Group 2: Clinical Trial Results - The first global Phase 2 clinical trial combining senolytic drugs with anti-PD-1 therapy showed a major pathological response rate of 33.3%, including a complete pathological response rate of 16.7%, significantly outperforming historical data for monotherapy [7] - The incidence of grade 3-4 adverse events was low at 4.2%, much lower than the 51% seen with chemotherapy combined with immunotherapy, indicating a favorable safety profile for the combination treatment [7] Group 3: Implications for Future Research - The findings provide valuable insights into the variability of tumor immune microenvironments and highlight the potential of targeting immune senescence to enhance anti-tumor efficacy [9] - The COIS-01 trial opens new avenues for combining immunotherapy with anti-aging strategies in the treatment of solid tumors, suggesting that enhancing immunity while reducing or reversing immune aging is a promising area for further exploration [9]