Local cues, local killers: human natural killer cells across tissues Natural killer (NK) cells are part of the innate immune system and reside in multiple tissues. During steady-state conditions, they contribute to tissue homeostasis, while in disease settings, tissue-resident (tr) NK cells are positioned at the frontline of immune surveillance. Due to their exposure to local microenvironments, NK cells residing outside the bloodstream exhibit phenotypic, transcriptional, functional, and metabolic features that distinguish them from their circulating counterparts. In this review, we outline the defining characteristics of tr NK cells, discuss their recirculation potential, and summarize their functional and metabolic specialization across human tissues. Finally, using cancer as an example, we highlight how tr NK cells are altered in disease and how local tissue environments shape their functional states.

Local cues, local killers: human natural killer cells across tissues #immunology

Exploiting immunogenic cell death to promote antitumor immunity Immunogenic cell death (ICD) converts the death of a tumor cell into an event sensed by the immune system. Recent studies show that distinct ICD modalities, including immunogenic apoptosis, pyroptosis, necroptosis, and hybrid forms such as PANoptosis, release defined sets of danger signals and cytokines that reshape the immune composition of the tumor microenvironment. In this review, we examine how ICD activates antitumor immunity and which immune cell subsets drive these responses. We also discuss how the benefits of ICD rely on its acute and transient nature, whereas prolonged or chronic exposure to the same inflammatory cues can ultimately dampen immune activation and promote oncogenesis. Finally, we outline the role of ICD and its clinical relevance in combination with immunotherapies.

Exploiting immunogenic cell death to promote antitumor immunity #immunology

Skull channels as gateways for immune surveillance of the brain The central nervous system (CNS), once considered immune privileged, is, in fact, protected by a dynamic immune compartment located in the meninges. These immune cells are crucial for brain protection, controlling neuroinflammation, and also supporting neural function. Recent studies show that meningeal immune cells, including myeloid and B cells, partly originate from the skull bone marrow, which communicates directly with the meninges via specialized skull channels identified in mice and humans. These channels allow immune cell trafficking and cerebrospinal fluid (CSF) exchange, positioning the skull marrow as a CSF-sensing niche. Therefore, understanding skull–meninges–brain interactions reveals a functional connection between bone marrow and the CNS, offering new insights into neuroimmune regulation and potential therapeutic strategies in neuroinflammatory conditions.

Skull channels as gateways for immune surveillance of the brain #immunology

Immunoferroptosis: ferroptosis meets tumor immunity and immunotherapy Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has attracted considerable attention in tumor biology and cancer therapy. Beyond its intrinsic role in tumor suppression, ferroptosis greatly influences the tumor immune microenvironment. Ferroptotic tumor cells release damage-associated molecular patterns, oxidized lipid mediators, and nucleic acids, which can either activate or suppress antitumor immunity. Conversely, immune cells modulate tumor cell sensitivity to ferroptosis through the secretion of cytokines and metabolites. In this review, we summarize the current understanding of the interplay between ferroptosis and tumor immunity. Targeting ferroptosis may offer broad opportunities to enhance tumor immunotherapy.

Immunoferroptosis: ferroptosis meets tumor immunity and immunotherapy #immunology

Trained immunity responses across infectious diseases and cancer vaccines Trained immunity (TRIM), a paradigm-shifting concept in immunology, refers to the long-term functional reprogramming of innate immune cells, enabling enhanced responsiveness to secondary challenges through metabolic and epigenetic remodeling. This phenomenon bridges the gap between innate and adaptive immunity, offering novel strategies for vaccine design that transcend traditional antigen-specific approaches. By exploiting the ‘memorylike’ properties of monocytes, macrophages, dendritic cells, neutrophils, and natural killer cells, next-generation vaccines aim to achieve broad-spectrum protection, prolonged durability, and heterologous immunity against pathogens and cancers. This review synthesizes recent advances in TRIM research in vaccines, focusing on its mechanisms, translational applications, and future directions in vaccinology.

Trained immunity responses across infectious diseases and cancer vaccines #immunology

Targeting TLR2 agonists as immunomodulators with broad antiviral activity Toll-like receptor-2 (TLR2) serves as an innate immune sensor that recognizes specific viral proteins, thereby initiating signaling pathways that can either enhance antiviral host defenses or induce pathological inflammatory responses. In this forum, we discuss the role of TLR2 and its agonists in enhancing antiviral and vaccine-induced immune responses.

Targeting TLR2 agonists as immunomodulators with broad antiviral activity #immunology

THEMIS: new insights into its evolution, structure, and function THEMIS (thymocyte-expressed molecule involved in selection) is the founding member of a family of metazoan proteins distinguished by the presence of a novel structural element designated the cysteine-containing all-beta-in-THEMIS (CABIT) module. Several studies have confirmed a critical role for THEMIS in T cell antigen receptor (TCR) signaling during T cell development, and more recent work has shown an important role for THEMIS in peripheral T cells. However, the molecular function of THEMIS in the TCR signaling pathway has long remained controversial due to conflicting experimental results. In this review article, we summarize recent data that provide new insights into the structure, evolution, and broader roles of the CABIT module, as well as clarify the molecular mechanism by which THEMIS influences TCR and cytokine receptor signaling in developing and mature T cells.

THEMIS: new insights into its evolution, structure, and function #immunology

Endothelial cells modulate immune cell responses during atherosclerosis Endothelial cells (ECs), which form the monolayer lining the vasculature, serve as critical gatekeepers of vascular homeostasis. They actively coordinate immune cell recruitment, adhesion, migration, and activation. Through tightly controlled expression and secretion of chemokines, cytokines, adhesion molecules, and immunomodulatory proteins, ECs locally orchestrate immune responses. In atherosclerosis, ECs contribute to plaque formation, plaque instability, and local inflammation by facilitating immune cell activation and transmigration into the plaque. However, ECs are highly heterogeneous, with their phenotype and function influenced by vascular localization and disease stage. EC subpopulations are transcriptionally distinct and adopt to either proinflammatory or angiogenic phenotypes and differentially participate in immune modulation. This review discusses recent insights into the immunomodulatory functions of ECs in atherosclerosis and underscores the importance of EC heterogeneity in understanding endothelial–immune cell interactions.

Endothelial cells modulate immune cell responses during atherosclerosis #immunology

Redefining nucleotide-binding oligomerization domain-like receptors: from immune sentinels to multifunctional regulators Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a large family of intracellular pattern recognition receptors primarily involved in innate immunity. Although canonical inflammasome-forming NLRs, such as NLRP3 and NLRC4, and microbial sensors, including NOD1 and NOD2, are well-characterized, the functions of many other NLRs remain poorly understood. This review article addresses this gap by highlighting the critical, context-dependent roles of these less-characterized NLRs beyond pathogen sensing. We classify these NLRs as immune modulators, regulators of autophagy and mitophagy, tissue-specific effectors, and reproductive mediators, expanding the traditional view of NLR functions. Understanding the diverse, context-dependent roles of NLRs across biological systems is essential to fully understand their complex regulatory networks and therapeutic potential, which extends beyond classical inflammasome functions.

Redefining nucleotide-binding oligomerization domain-like receptors: from immune sentinels to multifunctional regulators #immunology

Seven subsets, two fates: mouse γδ T cells in cancer immunity The importance of γδ T cells in cancer, as defenders against tumorigenesis, was established more than 2 decades ago. Since that time, research using mouse models of cancer has brought to light a nonuniform view of tumor-associated γδ T cells by providing granularity into the role of individual γδ T cell subsets in specific cancer types. In this review, we discuss data that highlight the unique contributions of Vγ1+, Vγ4+, Vγ5+, Vγ6+, and Vγ7+ cells throughout cancer progression. We delve into their responses to tumors, including both protective and pathogenic functions. We examine how the mechanisms by which these mouse immune cell subsets shape tumor development and spread can be exploited for therapeutic purposes in people with cancer.

Seven subsets, two fates: mouse γδ T cells in cancer immunity #immunology

Molecular determinants of NK cell memory Natural killer (NK) cells are innate lymphocytes uniquely equipped with stochastically expressed activating and inhibitory receptors that shape their cytotoxic potential. Although traditionally viewed as rapid and potent innate effectors against infected or transformed cells, we now appreciate that NK cells possess adaptive capabilities, such as antigen-specific clonal expansion and the generation of long-lived memory cells. The ability of NK cells to engage in innate and adaptive immune responses is tightly coordinated by a ‘three-signal’ framework that relies on the synergy between NK cell receptor engagement (signal 1), co-stimulation (signal 2), and cytokine-mediated signals (signal 3). This review focuses on knowledge gleaned from emerging molecular pathways aimed at modulating signals 1, 2, and 3 to reprogram NK cells for therapeutic utility.

Molecular determinants of NK cell memory #immunology

Charting the nerve–immune axis in endometriosis Endometriosis is increasingly recognized as a systemic disorder involving complex interactions between nerves and immune cells, driving chronic pain and inflammation beyond the initial theories. Recent breakthroughs highlight aberrant sensory nerve growth and dysfunctional immune responses as key events in lesion development and sustained pain. This review systematically examines the functional link between neuroimmune interplay and endometriosis, showing how reciprocal signaling between nerves and immune cells actively shapes epithelial and stromal behavior, amplifies inflammation, and reinforces pain circuitry. Recognizing this integrated neuroimmune framework reframes endometriosis as a disorder of distributed network dysregulation and highlights that targeting key neuroimmune nodes may offer new therapeutic opportunities to curb both lesion progression and endometriosis-related chronic pain.

Charting the nerve–immune axis in endometriosis #immunology

Diet-induced death: microbiome-mediated lipid stress reduces intestinal ILC3s Group 3 innate lymphoid cells (ILC3s) promote gastrointestinal health, dynamically interface with diet and microbes, and become impaired during chronic inflammation or metabolic syndrome. Torrico and colleagues uncover a key pathway rapidly disrupting ILC3 homeostasis in the intestines of humans and mice following the consumption of a high-fat diet.

Diet-induced death: microbiome-mediated lipid stress reduces intestinal ILC3s #immunology

Thank you to the Editors and Trends in Immunology for putting together this wonderful special issue on maternal–fetal & early-life immunity! ❤️

So nice to see a whole issue of @cp-trendsimmuno.bsky.social dedicated to the topic of perinatal and early life immunity, especially the great contribution by new people bringing new perspectives to this important but still grossly understudied developmental window

Image credit: Roberta Baldi (robertabaldi.com)

Special Issue from @cp-trendsimmuno.bsky.social: Perinatal and early life immunity.

Explore the full issue: www.cell.com/issue/S1471-...

The profound connection between mother & child reflects a dynamic immunological transformation that extends beyond gestation and early life.
Explore how maternal–fetal immunity & early-life exposures shape long-term health outcomes in our new special issue.
www.cell.com/immunology/c...

Our review is online! It highlights practical AI tools, key methods, and curated resources (website: yiquan2.com/AI-Immunolog... ) to empower experimentalists. We believe that the synergy between AI and experimental innovation will be a crucial catalyst for advancing the field of immunology.

The translational potential of studying bat immunity The author (A.T.I.) of this article would like to amend the following inadvertent error:

The translational potential of studying bat immunity #immunology

Postpandemic adjuvants to tailor vaccine-induced immunity Adjuvants are critical to improving the magnitude, breadth, functionality, and durability of vaccine immunogenicity. Despite advances in vaccinology, long-term immunity, variant cross-protection, and robust mucosal responses remain unmet goals. These challenges underscore the need for novel, safe, and effective adjuvants. This review explores emerging adjuvants targeting specific immune pathways. We highlight clinical and preclinical studies focusing on adjuvants that enhance durable and persistent humoral, cellular, and mucosal immunity. Current trends are discussed alongside tailored approaches for children and the elderly. Finally, the aim of this review is to highlight novel vaccine adjuvants currently in preclinical and clinical development, with the potential to generate a vaccine platform fit for the necessary yet unmet needs of public health in a postpandemic era.

Postpandemic adjuvants to tailor vaccine-induced immunity #immunology

The dual-adjuvant logic of mRNA vaccines Deciphering how mRNA vaccines generate humoral immunity could accelerate next-generation vaccine design. Castaño et al. reveal that mRNA–lipid nanoparticle vaccines employ a dual-adjuvant mechanism: nucleoside-modified mRNA triggers type I interferons to mature dendritic cells, while lipid nanoparticles induce a pro-T follicular helper cell program, together promoting robust germinal center responses.

The dual-adjuvant logic of mRNA vaccines #immunology

Experimental immunologists in the era of artificial intelligence While artificial intelligence (AI) is transforming biological science, its full potential in immunology has yet to be realized due to limited data and the need for extensive experimental validation. This review provides a practical guide for experimental immunologists to actively contribute to AI development, with a focus on applications for B- and T-cell receptors. It not only gives an overview of common AI techniques in immunology but also highlights the important role of high-throughput experimental methodologies. Overall, we believe that the synergy between AI and experimental innovation will be a crucial catalyst for advancing the field of immunology.

Experimental immunologists in the era of artificial intelligence #immunology

Molecular mechanisms of type 2 innate immune sensing Type 2 immunity protects against helminths and venoms, yet its dysregulation drives allergic diseases. Initiation occurs at barrier tissues, where epithelial cells detect perturbations and release alarmins, activating type 2 innate lymphoid cells and conditioning dendritic cells for T helper 2 priming. However, the framework of type 2 innate immune sensing remains largely incomplete. Critical gaps include the core immunostimulatory components of many stimuli and their host detection pathways. Recent advances, including tuft cell chemosensation, membrane pore formation as a common trigger, and the role of protein crystals and proteases in allergic inflammation, highlight emerging molecular principles. Unlike bacterial, viral, and fungal recognition via conserved molecular patterns, type 2 immunity often involves the sensing of perturbations and stress signals.

Molecular mechanisms of type 2 innate immune sensing #immunology

Decoding the immune–tumor synapse for data-driven design of next-generation immunotherapies The immunological synapse (IS) formed between cytotoxic CD8+ T lymphocytes (CTLs) and tumor cells represents the critical interface where many immunotherapies act, including therapeutic antibodies and chimeric antigen receptor immunotherapy. However, detailed characterization of the CTL–tumor IS has remained limited, primarily due to the transient and dynamic nature of this structure. Recent advances in proteomics, transcriptomics, high-throughput imaging, and machine learning are now enabling more precise investigation of this complex cell–cell interaction. This review highlights how emerging technologies have advanced our understanding of the CTL–tumor IS, outlines their potential to inform next-generation immunotherapies, and proposes future directions for technological innovation.

Decoding the immune–tumor synapse for data-driven design of next-generation immunotherapies #immunology

KLHL6: a proteostatic guardian against T-cell exhaustion Cheng et al.'s recent study identifies the Cullin3-RING E3 ubiquitin ligase complexes (CRL3) adaptor protein Kelch-like protein 6 (KLHL6) as a proteostasis regulator whose downregulation in chronically stimulated T cells leads to the accumulation of thymocyte selection-associated high mobility group box protein and phosphoglycerate mutase family member 5, driving T-cell dysfunction. This work positions T-cell exhaustion as a proteostatic disorder and highlights KLHL6 as a promising target for cancer immunotherapy.

KLHL6: a proteostatic guardian against T-cell exhaustion #immunology

The importance of long-lived IgE plasma cells for protracted allergies IgE contributes to allergy, but its cellular sources are rare and hard to identify. Genetic fate mapping and single-cell sequencing approaches have now revealed that two cell populations maintain IgE: long-lived IgE plasma cells (PCs) and ‘type 2’ memory B cells. This forum piece discusses recent discoveries on long-lived IgE PCs.

The importance of long-lived IgE plasma cells for protracted allergies #immunology

Barrier breakdown: insights into the skin–gut axis in psoriatic arthritis Psoriatic arthritis (PsA) is a chronic inflammatory disease that primarily affects the skin, joints, and entheses. Growing evidence implicates alterations at the gut and skin barriers in PsA pathogenesis. These sites play a crucial role in tissue homeostasis, and their disruption can contribute to the translocation of immune cells and bacterial products, resulting in systemic inflammation. Crosstalk between barrier sites and joints can promote or exacerbate disease development, with barriers also being a potential target of disease. This review article provides a barrier-centered perspective across gut, skin, and synovium, with a specific focus on new concepts about intertissue communication involving immune and microbial mediators that can propagate inflammation in PsA.

Barrier breakdown: insights into the skin–gut axis in psoriatic arthritis #immunology

Decoding brain border immunity to enable future therapeutic avenues The brain is no longer viewed as immunologically isolated but as an organ surrounded by dynamic border compartments that coordinate surveillance, drainage, and communication with the periphery. Key in...

🧠 Excited to share our review in Trends in Immunology (@cp-trendsimmuno.bsky.social): “Decoding brain border immunity to enable future therapeutic avenues.” by Lien Van Hoecke, @lorevanacker.bsky.social, and @roosvdb.bsky.social

www.cell.com/trends/immun...

Figure 1. Lactation-associated mammary T-cell adaptations and their potential roles in maternal and offspring health.

Lactation supports babies' immune health and reduces the risk of breast cancer for the mother. spkl.io/63327Avl8f

Abigail Jaquish & Deepshika Ramanan
@cp-trendsimmuno.bsky.social

Tumor-derived cystatin C enables amyloid clearance Li et al. described a tumor-derived neuroimmune mechanism that promotes clearance of established amyloid pathology in Alzheimer’s disease. Tumor-secreted cystatin C activates TREM2-dependent microglial phagocytosis, reducing plaques and improving cognition. This work introduces a context-dependent neuroimmune-modulatory strategy that shifts Alzheimer’s therapy from broad immune activation toward substrate-coupled amyloid clearance.

Tumor-derived cystatin C enables amyloid clearance #immunology