Volume 4 Issue 7封面解读彭敏/王猷光Rheumatoid arthritis is driven by tumor necrosis factor (TNF)—depicted on the cover as bamboo bees gnawing at bamboo joints, a metaphor for relentless cytokine-mediated articular destruction. Current anti-TNF biologics and protein degradation platforms all require repeated dosing, with efficacy progressively eroded by anti-drug antibody formation. The cover’s insect net, its mesh fused with a cellular outline, embodies the solution here: TNF receptor 1–based chimeric antigen receptor (CAR)-T cells with BCOR and ZC3H12A knockout (TNFR1TIF cells) function as living traps that continuously capture and internalize circulating TNF homotrimers via receptor-mediated endocytosis, degrading TNF without engaging host protein machinery. TNFR1TIF cells persisted for over one year in immunocompetent mice, reduced serum TNF to near wild-type levels, and conferred sustained rheumatoid arthritis remission from a single infusion—equivalent in efficacy to repeated high-dose adalimumab. This cellular-targeted protein degradation (TPD) platform shifts the paradigm from lifelong injections to a one-time, self-renewing intervention for chronic inflammatory disease.All Papers1. A collective roadmap for spatiotemporal omics in combating infections通信作者欧芷华、邓子卿This dialogue explores the transformative potential of spatiotemporal omics in reshaping the future of infectious disease research. Experts Zhihua Ou, Ziqing Deng, George Fu Gao, Andrea Cossarizza, Wenhong Zhang, and Aldo Tagliabue discussed the integration of multi-omics technologies to obtain high-resolution, dynamic, and spatiotemporal insights into disease pathogenesis. The conversation highlighted the key technical barriers that must be addressed for the broad application of spatiotemporal omics. Strategic research priorities were outlined, with a focus on diseases with high global burden and an emphasis on a “One Health” framework. The dialogue underscored the need to prioritize omics technologies based on specific biological questions and clinical goals. Major challenges in translating basic discoveries into clinical applications, such as data standardization, interdisciplinary collaboration, and ethical considerations, were also examined. Finally, the experts proposed strategies for the newly established SpatioTemporal Omics Consortium Infection Working Group to foster international collaboration through cultivating a shared vision, developing interoperable platforms, and securing sustainable funding to effectively integrate global scientific talent and resources for substantive innovations.引用Ou Z, Gao GF, Cossarizza A, et al . A collective roadmap for spatiotemporal omics in combating infections. hLife 2026; 4: 393–398.2. Cytomics-driven insights for investigating host–pathogen interactions通信作者Andrea CossarizzaRespiratory viral infections remain a significant global health burden, requiring interventions that establish robust defense directly at the portal of entry. Intranasal delivery of engineered IgM antibodies represents a highly potent platform for achieving mucosal protection. In this review, we evaluate the structural and functional rationale for prioritizing engineered IgM antibodies for mucosal immunity, provide preclinical evidence of their efficacy against respiratory viruses, and critically analyze the biomanufacturing and formulation strategies necessary for clinical translation. This review provides a comprehensiveroadmap for developing engineered IgM into a robust,variant-agnostic mucosal defense strategy against emergingand reemerging respiratory threats.引用Cossarizza A, Mussini C, Boraschi D, et al. Cytomics-driven insights for investigating host–pathogen interactions. hLife 2026; 4: 399–422.3. Targeted protein degradation via chimeric antigen receptor (CAR)-mediated antigen endocytosis in T cellshLife | 清华大学彭敏团队报道抗原降解型CAR-T细胞单次输注实现TNF持久降解长期缓解类风湿关节炎通信作者彭敏类风湿关节炎是一种以慢性关节炎症和进行性骨侵蚀为特征的全身性自身免疫病严重影响患者生活质量。肿瘤坏死因子是驱动RA病理进程的核心促炎细胞因子以阿达木单抗为代表的抗TNF生物制剂是临床一线疗法但需长期反复注射且慢性给药过程中产生的抗药抗体导致疗效进行性减退。从更宏观的视角来看包括LYTACs和KineTACs在内的所有现有靶向蛋白降解技术均依赖宿主细胞的内源性蛋白降解机器存在干扰正常生理代谢的潜在风险且均无法实现持久性降解效果。如何在不依赖宿主降解机制的前提下以单次给药实现致病蛋白的持续清除是慢性炎症疾病治疗领域亟待突破的核心科学命题。本研究实现了CAR-T细胞靶标从细胞表面抗原到可溶性胞外蛋白的范式性拓展建立了一种完全独立于宿主蛋白降解机器、单次输注即可实现持久效果的细胞性靶向蛋白降解平台。这一策略有望从根本上改变慢性炎症疾病的治疗模式——将“终身反复用药”转变为“一次干预、长期缓解”。引用Wang Y, He Z, Yin N, et al. Targeted protein degradation via chimeric antigen receptor (CAR)-mediated antigen endocytosis in T cells. hLife 2026; 4: 423–438.4. ZCF4-dependent suppression of MMP-9 drives virulence in fluconazole-resistant Candida aurishLife | 上海交大刘宁宁等研究团队揭示耐药耳念珠菌毒力增强机制并提出锌营养干预新策略通信作者潘磊、陈昌斌、王慧、刘宁宁耳念珠菌具有广谱适应性特点能够在人体不同部位如血液、皮肤、内脏器官等中定植在环境中存活时间久且难清除。因此深入揭示耳念珠菌在宿主体内的生存与致病机制显得尤为关键。在感染过程中宿主常启动“营养免疫”防御策略通过严格限制锌等必需微量元素的可用性使病原体营养匮乏从而抑制其生存。然而面对宿主体内的营养胁迫微环境耐药耳念珠菌是否具有特殊的适应机制这种特定的微环境压力如何驱动宿主与耳念珠菌之间的动态互作进而影响其毒力的变化这些关键科学问题目前仍有待深入探究。本研究揭示了耐药耳念珠菌在低锌条件下与宿主相互作用的机制提供了锌营养干预作为对抗耐药耳念珠菌的一种新策略为未来优化抗真菌治疗及临床干预提供了理论依据。引用Hong YM, Wang L, Yin ZJ, et al. ZCF4-dependent suppression of MMP-9 drives virulence in fluconazole-resistant Candida auris. hLife 2026; 4: 439–456.5. Polyfunctional varicella-zoster virus–reactive memory CD4 T cells reside in human bone marrow德国风湿免疫研究中心Andreas Radbruch院士团队发现人体骨髓存在具有多功能性水痘-带状疱疹病毒反应性记忆CD4⁺ T细胞通信作者Andreas Radbruch、董君水痘-带状疱疹病毒VZV是引发水痘和带状疱疹的病原体可在人体内潜伏数十年并在免疫功能下降时激活。由于机体对该病毒的控制主要依赖CD4⁺ T细胞科学家们一直以来在探索这种长期免疫记忆究竟储存在何处。本研究提出了一种免疫“分工”模式皮肤负责局部防御而骨髓则维持长期的全身性免疫记忆。该研究为理解人体如何长期控制VZV提供了新的视角也为降低带状疱疹发生风险的策略提供了一定理论依据。引用Wang Z, Reinke S, Shen Y, et al. Polyfunctional varicella-zoster virus–reactive memory CD4 T cells reside in human bone marrow. hLife 2026; 4: 457–460.6. Spatiotemporal omics: Revolutionizing infectious disease research通信作者欧芷华International Symposium on Spatiotemporal Omics for Infectious Diseases 2025 emphasized the potential of integrated omics platforms to revolutionize pathogen surveillance, mechanistic research, and translational medicine through specialized scientific programs and in-depth discussions. The establishment of the Spatiotemporal Omics Consortium Infection Working Group further strengthened the fields collaborative foundation by creating a global framework for data sharing, methodological standardization, and coordinated research efforts. To harness the full potential of spatiotemporal omics in infectious disease research, we must optimize technological protocols, strengthen knowledge exchange, prioritize key scientific challenges, secure funding, and launch international collaborative projects to accelerate basic research and clinical translation.引用Chen Z, Zhang P, Fang C, et al. Spatiotemporal omics: Revolutionizing infectious disease research. hLife 2026; 4: 461–462.