Over recent years, immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the clinical management of various solid neoplasms, including melanoma and lung carcinoma. A proportion of these malignancies e...Over recent years, immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the clinical management of various solid neoplasms, including melanoma and lung carcinoma. A proportion of these malignancies exhibit a baseline immunological configuration that can be successfully targeted with ICIs to support durable clinical responses. Conversely, breast neoplasms other than the triple-negative subset respond poorly to ICIs, reflecting numerous tumour-intrinsic and microenvironmental barriers against effective anticancer immunity. Notably, most hormone receptor-positive breast cancers tend to have limited immunogenicity and to establish a local and systemic immunosuppressive microenvironment that hinders responses to ICIs. Here, we summarize the main immunological features of human breast tumours, whenever possible comparing across disease subtypes, stages and treatment outcomes. Understanding the complex interplay between breast cancer, its hormonal regulation and the immune system will be essential for unlocking the full potential of ICIs and other immunotherapies in this oncological indication.
During an immune response, T cells face one of the most consequential decisions of their lifespan upon recognition of a ligand they have not previously encountered: whether to exit the naive basal state, undergo clonal e...During an immune response, T cells face one of the most consequential decisions of their lifespan upon recognition of a ligand they have not previously encountered: whether to exit the naive basal state, undergo clonal expansion and acquire effector functions. This process is often portrayed as a binary switch, in which naive cells from a highly diverse repertoire transition from an 'off' state to an 'on' state. However, this digital view overlooks the crucial prior information that T cells integrate through T cell receptor (TCR) interactions with self-peptide-MHC (self-pMHC). During thymic selection, immature T cells encounter a unique self-pMHC ligandome that shapes their development. After maturation, naive T cells continue to engage self-ligands as they patrol secondary lymphoid organs. Here we review evidence that these encounters with self-peptides are not only essential for T cell survival but also have lasting consequences that dynamically tune T cell function when called into action. The naive off state, therefore, is neither fixed nor functionally neutral. We argue that a deeper understanding of an individual's self-peptide repertoire is crucial for deciphering TCR self and non-self discrimination and for effectively harnessing T cell responses to foreign antigens.
Caspase activation platforms such as the apoptosome, inflammasome and PIDDosome are central to cellular responses to stress, coordinating inflammation, cell death and cell differentiation. Although each of these complexe...Caspase activation platforms such as the apoptosome, inflammasome and PIDDosome are central to cellular responses to stress, coordinating inflammation, cell death and cell differentiation. Although each of these complexes has been extensively studied in isolation, a comparative understanding of their structural and functional principles is lacking. Here we provide an integrated review of the architecture, activation mechanisms and signalling outputs of these supramolecular signalling platforms. All three of these platforms share a broadly conserved domain architecture and promote proximity-induced caspase activation, but they differ in their subcellular localization and upstream triggers. Furthermore, we explore differences in their downstream effectors and roles in immune signalling, cell cycle regulation and tissue homeostasis. Germline mutations in humans affecting these complexes are linked to cancer predisposition, immune dysregulation and neurodevelopmental disorders, respectively. Finally, we discuss therapeutic opportunities and unresolved questions, aiming to stimulate cross-disciplinary research and translational applications.
Once considered to be passive oxygen carriers, erythroid cells are now recognized as dynamic modulators of immune responses. Erythroid progenitors and precursors, collectively known as CD71⁺ erythroid cells, can suppress...Once considered to be passive oxygen carriers, erythroid cells are now recognized as dynamic modulators of immune responses. Erythroid progenitors and precursors, collectively known as CD71⁺ erythroid cells, can suppress innate and adaptive immune responses in neonates, in mothers during pregnancy, in chronic conditions such as cancer and autoimmunity, and during infection with viruses, including SARS-CoV-2 and HIV. Mature red blood cells engage pathogens directly, scavenge chemokines, cytokines and nucleic acids, and modulate immune functions through redox buffering and receptor-mediated interactions. The immune effects of red blood cells are highly context dependent, ranging from suppression to activation. This Review highlights the emerging field of erythroid-immune crosstalk and its translational potential in the settings of infection, cancer, pregnancy and chronic inflammatory conditions.
Plaza-Florido A, Carrera-Bastos P, Pérez-Prieto I
… +7 more, Fiuza-Luces C, Radom-Aizik S, Del Pozo Cruz B, Franceschi C, López-Soto A, López-Otín C, Lucia A
Centenarians - individuals aged 100 years or older - constitute a biologically distinct human population that achieves exceptional longevity while frequently retaining functional independence and avoiding major age-relat...Centenarians - individuals aged 100 years or older - constitute a biologically distinct human population that achieves exceptional longevity while frequently retaining functional independence and avoiding major age-related diseases or postponing their onset. Despite their advanced age, many centenarians show relatively preserved immune function and resistance to conditions linked to immunosenescence and chronic low-grade inflammation (inflammageing). These features are especially pronounced in semi-supercentenarians (105-109 years) and supercentenarians (≥110 years), whose immune profiles often resemble those of much younger individuals. In this Review, we explore how centenarians modulate key hallmarks of immune ageing across innate and adaptive immune compartments. We discuss evidence that they limit the pathological effects of inflammageing, potentially through reduced NLRP3 inflammasome activation, enhanced autophagy and a tempered senescence-associated secretory phenotype. Omics studies further reveal transcriptomic, epigenetic and microbial signatures consistent with preserved immune function, including youth-like gene expression patterns in circulating immune cells and beneficial shifts in gut microbiome composition. Together, these findings suggest that centenarians achieve longevity through coordinated adaptations that maintain immune homeostasis and disease resistance and may inform strategies to enhance healthspan in ageing societies.
Leishmania are intracellular protozoan parasites transmitted to humans by the bite of infected phlebotomine sand flies. Human infection is often asymptomatic but can develop into a broad spectrum of clinical diseases, co...Leishmania are intracellular protozoan parasites transmitted to humans by the bite of infected phlebotomine sand flies. Human infection is often asymptomatic but can develop into a broad spectrum of clinical diseases, collectively termed the leishmaniases. The underlying immunological features associated with asymptomatic infection and the varying clinical forms of disease have been extensively studied in pre-clinical models (including rodents, dogs and primates), as well as in human populations. Here, concentrating on data derived from human studies, we review the current understanding of how diverse lymphocyte-mediated immune responses drive the human disease spectrum seen following Leishmania infection.
Monocytes and macrophages are versatile immune sentinels that are present in nearly all tissues, where they continually adapt to local cues. In cancer, their functions are context-dependent - often linked to tumour growt...Monocytes and macrophages are versatile immune sentinels that are present in nearly all tissues, where they continually adapt to local cues. In cancer, their functions are context-dependent - often linked to tumour growth and poor prognosis but also capable of driving potent antitumour immunity. To explain this dichotomy, we frame cancer cells as 'infectious self', having both pathogen-like and self-like features. In turn, monocytes and macrophages adopt modular programmes across primary and metastatic tumour sites - as well as along haematogenous, lymphatic and transcoelomic routes of dissemination - that are shaped by oncogenic lesions, cancer cell differentiation states, tissue perturbations and organism-level variables. These cells are promising yet challenging therapeutic targets. Opportunities include blocking the recruitment, differentiation and scavenging activity of pro-tumour monocytes and macrophages; activating pattern recognition receptor signalling pathways and lymphocyte help; inducing cancer cell phagocytosis; and rewiring key intracellular signalling nodes. Emerging cellular and gene-based approaches - such as chimeric receptor engineering and in vivo target delivery - further expand this toolkit and underscore the potential to reprogramme monocyte and macrophage responses for durable control of solid tumours.
Tissue-resident macrophages are crucial sentinel cells of the innate immune system that sense nutrient fluctuations and orchestrate adaptive responses to support steady-state metabolic homeostasis. When dysregulated, the...Tissue-resident macrophages are crucial sentinel cells of the innate immune system that sense nutrient fluctuations and orchestrate adaptive responses to support steady-state metabolic homeostasis. When dysregulated, these cells have major roles in the pathogenesis of numerous diseases, including obesity-associated metabolic diseases such as type 2 diabetes, metabolic dysfunction-associated fatty liver disease and atherosclerotic cardiovascular disease. Cellular and phenotypic remodelling of macrophage populations in response to metabolic alterations linked to obesity perturbs homeostatic interactions and promotes low-grade sterile tissue inflammation, which propagates tissue dysfunction. Much of the seminal initial work in the field of 'immunometabolism' explored the role of metabolic pathways in the regulation of distinct immune cell types. More recently, however, it has become appreciated that intermediary metabolites can function as signals that regulate macrophages at the level of the whole tissue or organism. As we discuss here, recent work has identified intermediary metabolites such as lactate, succinate and itaconate, and nutrients including glucose, amino acids and free fatty acids, as crucial regulatory signals that control macrophage function in obesity and metabolic disease.
Cytokines are essential mediators of immune functions and regulate many other biological processes, ranging from fetal development to ageing. Dysregulation of cytokine responses can substantially increase the risk of dis...Cytokines are essential mediators of immune functions and regulate many other biological processes, ranging from fetal development to ageing. Dysregulation of cytokine responses can substantially increase the risk of disease and so their activity requires tight control. The formation of cytokine homodimers, heterodimers and multimers has evolved as a versatile mechanism to regulate cytokine biology, in which multimerization can enable or attenuate their activity, diversify signalling outcomes and drive signalling bias. Here, we discuss the structure-function implications of cytokine multimerization for type I cytokines (for example, the IL-6 and IL-12 cytokine families), type II cytokines (for example, the IL-10 and interferon families), cytokines that signal through immunoglobulin-family receptors (for example, the IL-1 and M-CSF families) and also for the IL-17, TNF and TGFβ cytokine families. We highlight the influence of multimerization on cytokine activity and receptor engagement, as well as the relevance of cytokine multimerization for disease development and the resulting therapeutic opportunities.
The liver, a key metabolic organ, has a central role in maintaining systemic homeostasis but is vulnerable to numerous diseases. Its metabolic functions are mainly carried out by hepatocytes; however, the liver also harb...The liver, a key metabolic organ, has a central role in maintaining systemic homeostasis but is vulnerable to numerous diseases. Its metabolic functions are mainly carried out by hepatocytes; however, the liver also harbours diverse non-parenchymal cell populations, including immune cells. Among these, Kupffer cells, the resident macrophages of the liver, are critical modulators of liver function and immunity. Emerging research highlights their dynamic roles throughout life, from maintaining tissue homeostasis to shaping the balance between immune tolerance and activation in adulthood. Kupffer cells are located in liver sinusoids, where they act as frontline defenders, clearing pathogens and cellular debris from the circulation. Beyond their established phagocytic and immune regulatory functions, Kupffer cells influence metabolic processes, tissue repair and oncogenesis. Moreover, they shape the response of the liver to metabolic disorders such as metabolic dysfunction-associated steatohepatitis, infections and malignancies, including hepatocellular carcinoma. Here we explore Kupffer cell biology, focusing on the development, heterogeneity and multifaceted roles of these cells in liver health and disease. We further discuss how advances in imaging, transcriptomics and macrophage-targeted therapies can inform future strategies to combat liver-associated health challenges.