Seminars in Immunology最新文献

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Neurotransmitters: Key regulators of the tumor immune microenvironment 神经递质：肿瘤免疫微环境的关键调节因子

IF 7.8 2区医学 Q1 IMMUNOLOGY

Seminars in Immunology

Pub Date : 2026-01-29 DOI: 10.1016/j.smim.2026.102015

Liubo Zhang , Wei Jing , Yunbo Li , Yu Ping , Yi Zhang

Recent studies have revealed that neurotransmitters, as a class of important signaling molecules, have functional roles that extend beyond the traditional nervous system and play critical regulatory functions in the tumor immune microenvironment. Research has demonstrated that various classical neurotransmitters and their receptors are widely expressed in tumor tissues. Through complex receptor-mediated signaling networks, neurotransmitters dynamically regulate the functions of diverse cell types, including tumor cells and immune cells, thereby influencing tumor progression. Based on these discoveries, significant progress has been made in developing innovative drugs targeting neurotransmitter-receptor axes. Multiple agents, such as N-methyl-D-aspartate receptor (NMDAR), γ-aminobutyric acid-A (GABA-A) agonists, and dopamine receptor antagonists, have demonstrated promising antitumor effects in both preclinical studies and clinical trials. This review systematically summarizes the multidimensional regulatory mechanisms of neurotransmitters in tumor immunity and comprehensively discusses recent advances in neurotransmitter-targeted therapies. These findings not only provide a theoretical foundation for developing novel immunotherapeutic strategies based on neurotransmitter modulation but also open new research perspectives for understanding the emerging field of "neuro-immune-tumor" crosstalk.

近年来的研究表明，神经递质作为一类重要的信号分子，其功能作用超出了传统的神经系统，在肿瘤免疫微环境中起着至关重要的调节作用。研究表明，多种经典神经递质及其受体在肿瘤组织中广泛表达。神经递质通过复杂的受体介导的信号网络，动态调节多种细胞类型的功能，包括肿瘤细胞和免疫细胞，从而影响肿瘤的进展。基于这些发现，在开发针对神经递质受体轴的创新药物方面取得了重大进展。n -甲基- d-天冬氨酸受体（NMDAR）、γ-氨基丁酸-a （gaba -）激动剂和多巴胺受体拮抗剂等多种药物在临床前研究和临床试验中均显示出良好的抗肿瘤效果。本文系统综述了神经递质在肿瘤免疫中的多维调控机制，并全面讨论了神经递质靶向治疗的最新进展。这些发现不仅为开发基于神经递质调节的新型免疫治疗策略提供了理论基础，而且为理解新兴的“神经-免疫-肿瘤”串扰领域开辟了新的研究视角。

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引用次数: 0

Diverse IL-9-secreting T helper cells direct responses in the allergic lung 多种il -9分泌T辅助细胞直接反应过敏性肺

IF 7.8 2区医学 Q1 IMMUNOLOGY

Seminars in Immunology

Pub Date : 2026-01-14 DOI: 10.1016/j.smim.2026.102014

Kaitlyn G. Jackson, Mark H. Kaplan

IL-9 promotes airway hyperresponsiveness, eosinophilia, mast cell expansion, and antibody-mediated inflammation through interactions with mast cells, eosinophils, B cells, and airway and lung macrophages in models of allergic airway disease. IL-9 has increasingly been linked to asthma severity in patients. Early studies primarily focused on the differentiation of "classical" Th9 cells, which express IL-9 but not other type II cytokines. Recent research has identified additional populations of IL-9-secreting CD4⁺ T cells, including Th2-allergic (Th2A) cells and resident memory Th9 (Th9rm) cells. Despite IL-9 induction in classical Th9 effector cells being transient, Th2A and memory populations generate a recall IL-9 response upon repeated allergen exposure. Additionally, cytokine-driven bystander activation may prolong IL-9 production in various CD4⁺ T cell subsets. This review evaluates the transcriptional, metabolic, and cytokine-mediated signals that regulate the effector function of IL-9-secreting CD4⁺ T cell subsets in models of acute, chronic, and intermittent allergic airway disease. Given the heterogeneity of asthma phenotypes, identifying endotypes characterized by high levels of Th9 cells or IL-9 may improve therapeutic precision in asthma treatment.

在变应性气道疾病模型中，IL-9通过与肥大细胞、嗜酸性粒细胞、B细胞、气道和肺巨噬细胞的相互作用，促进气道高反应性、嗜酸性粒细胞增多、肥大细胞扩增和抗体介导的炎症。IL-9与患者哮喘严重程度的关系越来越密切。早期的研究主要集中在“经典”Th9细胞的分化上，这些细胞表达IL-9而不表达其他II型细胞因子。最近的研究发现了分泌il -9的CD4+ T细胞的其他群体，包括th2过敏（Th2A）细胞和常驻记忆Th9 （Th9rm）细胞。尽管IL-9在经典Th9效应细胞中的诱导是短暂的，但Th2A和记忆群体在反复暴露于过敏原后会产生回忆性IL-9反应。此外，细胞因子驱动的旁观者激活可能延长各种CD4+ T细胞亚群中IL-9的产生。本综述评估了在急性、慢性和间歇性变应性气道疾病模型中调节il -9分泌CD4+ T细胞亚群效应功能的转录、代谢和细胞因子介导的信号。鉴于哮喘表型的异质性，鉴定以高水平Th9细胞或IL-9为特征的内型可能提高哮喘治疗的治疗精度。

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引用次数: 0

New insights into Th9 cells in inflammatory bowel diseases 炎症性肠病中Th9细胞的新认识

IF 7.8 2区医学 Q1 IMMUNOLOGY

Seminars in Immunology

Pub Date : 2025-12-16 DOI: 10.1016/j.smim.2025.102013

Markus F. Neurath

The involvement of T helper cells in the pathogenesis of inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, has been a subject of considerable research interest. The clinical picture of IBD is characterised by chronic intestinal inflammatory processes that may lead to complications such as stenoses, abscesses, fistulas and colorectal cancer. Recent findings have indicated that T helper 9 (Th9) cells, which secrete the cytokine IL-9, play a role in the pathogenesis of IBD. These cells have been observed to damage the intestinal epithelium by IL-9 production and to amplify the mucosal inflammatory immune response by activating other immune cells. Studies utilising murine models of chronic intestinal inflammation have demonstrated that targeting IL-9 or Th9 cells can alleviate inflammatory responses. In consideration of these findings, it will be of interest to delve into the potential of neutralizing IL-9 function as a therapeutic intervention for patients suffering from IBD.

T辅助细胞参与炎性肠病（IBD）的发病机制，包括克罗恩病和溃疡性结肠炎，一直是一个相当有研究兴趣的主题。IBD的临床特征是慢性肠道炎症过程，可能导致诸如狭窄、脓肿、瘘管和结直肠癌等并发症。最近的研究表明，分泌细胞因子IL-9的辅助性T细胞9 （Th9）在IBD的发病过程中起作用。已观察到这些细胞通过产生IL-9损害肠上皮，并通过激活其他免疫细胞放大粘膜炎症免疫反应。利用小鼠慢性肠道炎症模型的研究表明，靶向IL-9或Th9细胞可以减轻炎症反应。考虑到这些发现，深入研究中和IL-9功能作为IBD患者治疗干预的潜力将是很有意义的。

引用次数: 0

Targeting immune heterogeneity in liver metastases through in vivo genetic engineering 通过体内基因工程靶向肝转移的免疫异质性。

IF 7.8 2区医学 Q1 IMMUNOLOGY

Seminars in Immunology

Pub Date : 2025-12-15 DOI: 10.1016/j.smim.2025.102012

Giovanna Giacca, Mario Leonardo Squadrito

The liver is both a central metabolic organ and a uniquely tolerogenic immune niche, which makes it a frequent site of liver metastases (LMS) and a challenging environment for immunotherapy. It is increasingly appreciated that resident liver cells- Kupffer cells, Ito cells, liver sinusoidal endothelial cells - as well as infiltrating myeloid and lymphoid populations, collectively establish an immunosuppressive microenvironment that favors metastatic seeding and progression. Advances in our understanding of these cell-cell interactions and the exclusion of effector T cells, have highlighted new therapeutic entry points. In parallel, innovations in gene-delivery platforms, from lentiviral and AAV vectors to lipid nanoparticles, and in engineered immune cells such as CAR-T and CAR-NK cells, are opening avenues to modulate the hepatic tumor niche. Here we review how these insights into liver immunobiology inform the design of next-generation immunotherapies for LMS, emphasizing opportunities and challenges in translating them to the clinic.

肝脏既是一个中心代谢器官，又是一个独特的耐受性免疫生态位，这使得它成为肝转移（LMS）的常见部位和免疫治疗的一个具有挑战性的环境。人们越来越认识到，驻留的肝细胞——Kupffer细胞、Ito细胞、肝窦内皮细胞——以及浸润的骨髓和淋巴细胞群体，共同建立了一个免疫抑制微环境，有利于转移的播种和进展。我们对这些细胞间相互作用和排除效应T细胞的理解的进步，突出了新的治疗切入点。与此同时，基因传递平台的创新，从慢病毒和AAV载体到脂质纳米颗粒，以及工程免疫细胞（如CAR-T和CAR-NK细胞），正在开辟调节肝脏肿瘤生态位的途径。在这里，我们回顾了这些肝脏免疫生物学的见解如何为LMS下一代免疫疗法的设计提供信息，强调了将其转化为临床的机遇和挑战。

引用次数: 0

The role of non-cancer cell infections in oncolytic virus therapy 非癌细胞感染在溶瘤病毒治疗中的作用。

IF 7.8 2区医学 Q1 IMMUNOLOGY

Seminars in Immunology

Pub Date : 2025-12-02 DOI: 10.1016/j.smim.2025.101998

Jahanara Rajwani , Douglas J. Mahoney

Oncolytic viruses (OV) are designed to seek out and kill cancer cells, while simultaneously inciting potent antitumour immunity. While their exact mechanism of action is incompletely understood, therapeutic activity is proposed to rely on viruses selectively infecting cancer cells – not only to debulk the tumour, but also to elicit immunogenic cell death (ICD) of cancer cells and subsequent antigen-specific immunity. However, despite being engineered for cancer cell selectivity, several studies have demonstrated OV-induced antitumour activity against tumours that do not robustly support virus infection in vivo. Further, many non-malignant cells within, and outside of, the tumour microenvironment (TME) have been shown to support OV infection, and in some cases, contribute to tumour regression. These unexpected findings warrant a more comprehensive understanding of the mechanisms by which OV-infected non-cancer cells elicit antitumour activity. Thus, in this review, we aim to summarize current knowledge on the role of non-cancer cell infections in OV therapy. We focus our attention primarily on infected non-cancer cells in the TME, including endothelial cells, fibroblasts and perivascular cells, as well as those in secondary lymphoid organs (spleen and lymph nodes). In addition, we include a brief commentary on the impact of liver and peripheral blood mononuclear cell infections. Interestingly, while the consequences of some non-malignant cell infections appear to be similar across multiple OVs, the outcome of other infections are OV-specific. This highlights the need to better understand cellular infections for each OV, in order to leverage this information for the development of next generation OV platforms.

溶瘤病毒（OV）被设计用来寻找和杀死癌细胞，同时激发有效的抗肿瘤免疫。虽然它们的确切作用机制尚不完全清楚，但有人提出，治疗活性依赖于病毒选择性地感染癌细胞——不仅可以使肿瘤脱落，还可以引起癌细胞的免疫原性细胞死亡（ICD）和随后的抗原特异性免疫。然而，尽管被设计为癌细胞选择性，一些研究已经证明ov诱导的抗肿瘤活性针对体内不支持病毒感染的肿瘤。此外，肿瘤微环境（TME）内外的许多非恶性细胞已被证明支持OV感染，在某些情况下，有助于肿瘤消退。这些意想不到的发现为更全面地了解ov感染的非癌细胞引发抗肿瘤活性的机制提供了依据。因此，在这篇综述中，我们旨在总结非癌细胞感染在OV治疗中的作用。我们主要关注TME中感染的非癌细胞，包括内皮细胞、成纤维细胞和血管周围细胞，以及次要淋巴器官（脾脏和淋巴结）中的细胞。此外，我们还包括对肝脏和外周血单核细胞感染的影响的简要评论。有趣的是，虽然一些非恶性细胞感染的结果在多个OVs中似乎是相似的，但其他感染的结果是ov特异性的。这凸显了更好地了解每种OV的细胞感染的必要性，以便利用这些信息开发下一代OV平台。

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引用次数: 0

IL-1 family members as regulators of lymphoid type-2 immunity in cancer IL-1家族成员在癌症中作为淋巴2型免疫的调节因子

IF 7.8 2区医学 Q1 IMMUNOLOGY

Seminars in Immunology

Pub Date : 2025-11-28 DOI: 10.1016/j.smim.2025.102005

Stefania Roma , Filippo Colombo , Lucia De Monte , Maria Pia Protti

IL-1 family members, such as IL-1 and IL-33, are present in the tumor microenvironment and exert tumor-intrinsic and tumor-extrinsic functions with both pro- and anti-tumor effects. Among their immunoregulatory roles, both cytokines contribute to lymphoid type-2 immunity. IL-1 can indirectly promote CD4⁺ Th2 responses by inducing thymic stromal lymphopoietin production by tumor cells or cancer associated fibroblasts that conditions Th2-polarizing dendritic cells, whereas IL-33 is a potent direct activator of CD4⁺ Th2 and other type-2 immune cells, such as group 2 innate lymphoid cells (ILC2s). In a large majority of established human cancers, CD4⁺ Th2 cell responses correlate with tumor-promotion, whereas expansion of ILC2s can either suppress or promote tumor immunity in a more balanced way, leading to tumor progression or regression. Interestingly, the two prototypical Th2 cytokines IL-13 and IL-5 exert apparently pro- and anti-tumor opposing functions by recruitment of myeloid-derived cells and eosinophils, respectively. In addition, anti-tumor ILC2s under the influence of the tumor microenvironment may become dysfunctional, ultimately resulting in tumor-progression. Understanding the specific cancer context and considering the similarities as well as the distinctive features of the two lymphoid type-2 cell subsets is essential for developing effective immunotherapeutic strategies by targeting the IL-1 and IL-33 cytokines.

IL-1家族成员，如IL-1和IL-33，存在于肿瘤微环境中，发挥肿瘤内源性和肿瘤外源性功能，具有促肿瘤和抗肿瘤作用。在它们的免疫调节作用中，这两种细胞因子都有助于淋巴细胞2型免疫。IL-1可以通过诱导肿瘤细胞或肿瘤相关成纤维细胞产生胸腺基质淋巴生成素间接促进CD4+ Th2反应，而IL-33是CD4+ Th2和其他2型免疫细胞（如2组先天淋巴样细胞（ILC2s））的有效直接激活剂。在大多数已确定的人类癌症中，CD4+ Th2细胞反应与肿瘤促进相关，而ILC2s的扩增可以以更平衡的方式抑制或促进肿瘤免疫，导致肿瘤进展或消退。有趣的是，两种典型的Th2细胞因子IL-13和IL-5分别通过募集髓源性细胞和嗜酸性粒细胞发挥明显的促肿瘤和抗肿瘤作用。此外，抗肿瘤ILC2s在肿瘤微环境的影响下可能功能失调，最终导致肿瘤进展。了解特定的癌症背景，考虑两种淋巴样2型细胞亚群的相似性和独特特征，对于开发针对IL-1和IL-33细胞因子的有效免疫治疗策略至关重要。

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引用次数: 0

HBV antigen as a tumour antigen in adoptive TCR-T cell therapy for HBV-related HCC: rationale and clinical effectiveness HBV抗原作为肿瘤抗原在HBV相关HCC过继TCR-T细胞治疗中的作用：理论基础和临床效果

IF 7.8 2区医学 Q1 IMMUNOLOGY

Seminars in Immunology

Pub Date : 2025-11-06 DOI: 10.1016/j.smim.2025.102004

Shan He, Anthony T. Tan, Antonio Bertoletti

Hepatocellular carcinoma developing in patients with HBV chronic infection are marked by expression of whole or partial HBV antigens through a highly tissue-specific process, determined by the hepatotropism of HBV. HBV antigens are therefore a possible target for adoptive T cell immunotherapy as their expression and, consequently, potential on-target off-tumour events, are confined to the liver compartment with no involvement of other organs. Here we summarise the research steps to develop T cell therapy that utilises viral antigen as a tumour antigen in HBV-related HCC and discuss the efficacy and the potential mechanisms of action of HBV-specific T cell receptor (TCR)-redirected T cells in phase I clinical trials.

HBV慢性感染患者发生肝细胞癌的标志是通过一个高度组织特异性的过程表达全部或部分HBV抗原，这是由HBV的嗜肝性决定的。因此，HBV抗原是过继性T细胞免疫治疗的可能靶标，因为它们的表达和潜在的靶外肿瘤事件局限于肝室，不涉及其他器官。在这里，我们总结了利用病毒抗原作为肿瘤抗原在hbv相关HCC中开发T细胞疗法的研究步骤，并讨论了hbv特异性T细胞受体（TCR）重定向T细胞在I期临床试验中的疗效和潜在作用机制。

引用次数: 0

TH9 cells and interleukin-9 in parasitic infections: Updates, opportunities, and challenges 寄生虫感染中的TH9细胞和白细胞介素-9：最新进展、机遇和挑战

IF 7.8 2区医学 Q1 IMMUNOLOGY

Seminars in Immunology

Pub Date : 2025-11-01 DOI: 10.1016/j.smim.2025.102003

Javier Orozco-Cordoba, Cleofas Marcial-Medina, Paula Licona-Limón

Over the past decades, Interleukin-9 (IL-9) and T_H9 cells, have gained attention as important regulators of diverse responses throughout the promotion of activation and expansion of diverse cell subtypes. T_H9 cells have been studied in several immunological contexts, including allergic and autoimmune responses, cancer and infectious diseases; being the latest one, specifically those induced by parasites, the main focus of this review. T_H9 cells have risen as critical mediators of the immune response against parasites, including roundworms, flatworms, tapeworms, and hookworms; however, the number of parasitic diseases influenced by this cell subset was still limited in studies published up to 2016. In this review, we aimed to summarize the latest findings regarding the roles of T_H9 cells and IL-9 in parasitic infections, seeking to provide a comprehensive overview of latest knowledge in the field including the models of parasites never studied. We compile recent evidence highlighting both protective and pathogenic roles for IL-9, discuss the challenges to unravel the complexity of T_H9-IL-9 mediated responses during parasitic infections, as well as the opportunities for therapeutic intervention that will help to translate new findings into future clinical applications.

在过去的几十年里，白细胞介素-9 （IL-9）和TH9细胞作为促进多种细胞亚型激活和扩增的多种反应的重要调节因子而受到关注。TH9细胞已在多种免疫学背景下被研究，包括过敏和自身免疫反应、癌症和传染病；这是最新的一种，特别是寄生虫引起的，是本文的重点。TH9细胞已成为针对寄生虫（包括蛔虫、扁虫、绦虫和钩虫）的免疫反应的关键介质；然而，截至2016年发表的研究中，受该细胞亚群影响的寄生虫病数量仍然有限。在本文中，我们旨在总结有关TH9细胞和IL-9在寄生虫感染中的作用的最新发现，以期对该领域的最新知识提供一个全面的概述，包括从未研究过的寄生虫模型。我们收集了最近的证据，强调IL-9的保护和致病作用，讨论了在寄生虫感染期间揭示TH9-IL-9介导反应的复杂性的挑战，以及治疗干预的机会，这将有助于将新发现转化为未来的临床应用。

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引用次数: 0

Interleukin-1β and cancer immune response 白细胞介素-1β与癌症免疫反应

IF 7.8 2区医学 Q1 IMMUNOLOGY

Seminars in Immunology

Pub Date : 2025-11-01 DOI: 10.1016/j.smim.2025.102002

Cédric Rébé, François Ghiringhelli

IL-1β belongs to the IL-1 family and has the particularity to need to be cleaved by caspase-1 to be active. Once processed, IL-1β is secreted and binds to IL-1R1 on target cells, leading to the transcription of specific genes. Within a tumor, IL-1β is produced and secreted by various cell types, such as immune cells, fibroblasts or cancer cells and has pleiotropic effects on immune cells, angiogenesis, cancer cell proliferation, migration and metastasis. Thus, depending on the cancer type, the treatments or the tumor microenvironment (TME), IL-1β has opposite effects on cancer progression, thus raising the question of inducing or inhibiting IL-1β. Here, we will analyze the impact of IL-1β on cancer cells and immune cells of the TME in different types of cancers.

IL-1β属于IL-1家族，具有需要被caspase-1切割才能激活的特殊性。一旦加工，IL-1β被分泌并与靶细胞上的IL-1R1结合，导致特定基因的转录。在肿瘤内，IL-1β由多种细胞类型（如免疫细胞、成纤维细胞或癌细胞）产生和分泌，对免疫细胞、血管生成、癌细胞增殖、迁移和转移具有多种作用。因此，根据癌症类型，治疗或肿瘤微环境（TME）， IL-1β对癌症进展具有相反的作用，从而提出了诱导或抑制IL-1β的问题。在这里，我们将分析IL-1β对不同类型癌症的癌细胞和TME免疫细胞的影响。

引用次数: 0

Antiviral humoral immunity: Enemy or ally of viral immunotherapy? 抗病毒体液免疫：病毒免疫治疗的敌人还是盟友？

IF 7.8 2区医学 Q1 IMMUNOLOGY

Seminars in Immunology

Pub Date : 2025-10-24 DOI: 10.1016/j.smim.2025.102001

Maria Eugenia Davola, Olga Cormier, Karen Mossman

Oncolytic viruses are gaining traction as novel cancer immunotherapy tools given their ability to selectively target transformed cells. While direct tumor debulking was historically considered their primary mode of action, it is now appreciated that antitumor immunity significantly contributes to therapeutic efficacy. While T cells play a key role, less is known about humoral immunity in oncolytic virotherapy. While systemic delivery is the clinically preferred route for therapy administration, most oncolytic viruses are delivered directly to the tumor to avoid neutralization by pre-existing or therapy-induced immunity. In this review, we discuss emerging data showing the contribution of antiviral immunity to oncolytic activity along with growing evidence that questions dogma surrounding inhibitory activity of neutralizing antibodies. We further discuss how route of administration, tumor vascularization, host and cellular range, and oncolytic virus mechanism of action influence the role of the humoral immune response to therapy outcomes. We end the discussion with additional factors to consider, such as regulatory B cells, immunoglobulin isotype, Fc-mediated functions and the importance of choosing the right pre-clinical model that may contribute to overall therapy outcomes that are not routinely considered in pre-clinical and clinical studies of viral immunotherapies.

溶瘤病毒具有选择性靶向转化细胞的能力，因此作为新型癌症免疫治疗工具越来越受到关注。虽然直接肿瘤减体积历来被认为是它们的主要作用方式，但现在人们认识到抗肿瘤免疫显著有助于治疗效果。虽然T细胞发挥了关键作用，但对溶瘤病毒治疗中的体液免疫知之甚少。虽然全身给药是临床首选的治疗途径，但大多数溶瘤病毒是直接给药到肿瘤中，以避免被预先存在的或治疗诱导的免疫中和。在这篇综述中，我们讨论了显示抗病毒免疫对溶瘤活性的贡献的新数据，以及越来越多的证据，质疑围绕中和抗体抑制活性的教条。我们进一步讨论了给药途径、肿瘤血管化、宿主和细胞范围以及溶瘤病毒的作用机制如何影响体液免疫反应对治疗结果的作用。我们以其他需要考虑的因素结束讨论，如调节性B细胞、免疫球蛋白同型、fc介导的功能，以及选择正确的临床前模型的重要性，这些模型可能有助于整体治疗结果，而这些在病毒免疫治疗的临床前和临床研究中通常没有考虑到。

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引用次数: 0

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