Interleukin-33 (IL-33) is classically viewed as an alarmin, but in cancer, it may do more than merely initiate immunity. I propose that IL-33 scripts the trajectory of immunity through interconnected regulatory layers th...Interleukin-33 (IL-33) is classically viewed as an alarmin, but in cancer, it may do more than merely initiate immunity. I propose that IL-33 scripts the trajectory of immunity through interconnected regulatory layers that influence how host responses are organized and ultimately resolved into either productive antitumor immunity or suppressive, repair-like states.
Mitochondrial calcium (mtCa) has long been framed as a bioenergetic regulator, yet evidence redefines it as a relevant immunometabolic switch. Within the tumor microenvironment, the mitochondrial calcium uniporter (MCU)...Mitochondrial calcium (mtCa) has long been framed as a bioenergetic regulator, yet evidence redefines it as a relevant immunometabolic switch. Within the tumor microenvironment, the mitochondrial calcium uniporter (MCU) complex and the NCLX-TMEM65 efflux axis maintain a 'Goldilocks zone' of Ca homeostasis. This can be exploited by cancer cells to sustain oxidative phosphorylation and tricarboxylic acid-derived oncometabolite production, including succinate, fumarate, and 2-hydroxyglutarate, while imposing ionic and nutrient constraints on infiltrating immune cells. Chronic mtCa overload in effector T cells drives mitochondrial dysfunction and exhaustion, while oxidative phosphorylation-dependent Ca flux enforces the acquisition of an immunosuppressive profile in macrophages. Disrupting these tumor-immune ionic imbalances through selective MCU modulation or efflux pathway targeting offers a strategy to restore immune surveillance and/or enhance immune checkpoint inhibitor therapies.
Antibody-drug conjugates (ADCs) selectively deliver potent chemotherapeutic agents to tumor cells. In clinical settings, the therapeutic benefits of ADCs can be improved when combined with immune checkpoint inhibitors, p...Antibody-drug conjugates (ADCs) selectively deliver potent chemotherapeutic agents to tumor cells. In clinical settings, the therapeutic benefits of ADCs can be improved when combined with immune checkpoint inhibitors, probably due to the immunogenic nature of ADC-induced tumor cell death, which releases tumor antigens to be cross-presented by conventional type-1 dendritic cells (cDC1). This opinion article proposes that cDC1-mediated cross-presentation and cross-priming represent a central, still poorly understood, and underexploited immunological mechanism that links ADC-induced tumor cell death to durable antitumor immunity. Such mechanisms open opportunities for combinations with established and experimental immunomodulatory agents. Aside from checkpoint inhibitors, synergy has also been observed with agonist monoclonal antibodies directed to costimulatory receptors, increasing the potency of the ensuing antitumor immune response.
Growing evidence indicates that gut microbiota-derived metabolites are key regulators of immunometabolism in inflammatory bowel disease (IBD). Intestinal epithelial cells and immune cells exhibit profound metabolic alter...Growing evidence indicates that gut microbiota-derived metabolites are key regulators of immunometabolism in inflammatory bowel disease (IBD). Intestinal epithelial cells and immune cells exhibit profound metabolic alterations in IBD. Microbial metabolites act as intermediates in host-microbe communication, reshaping mitochondrial functions and cellular metabolic pathways, thereby impacting immune functions. Dysbiosis may, therefore, perturb immune homeostasis by rewiring host metabolic circuits. Understanding how microbial metabolites orchestrate immunometabolic crosstalk in the gut and leveraging it to recalibrate host immunometabolic circuits represents promising, underexplored therapeutic avenues. In this review, we highlight emerging concepts on how gut microbiota-derived metabolites shape immune cell immunometabolism and discuss the therapeutic potential of targeting the microbiota-metabolite-immunometabolism axis in IBD.
Inflammation is a metabolically intensive and tightly regulated process, driven primarily by innate immune cells. Cellular metabolism actively instructs immune signaling and cell fate decisions. Bioenergetic pathways, in...Inflammation is a metabolically intensive and tightly regulated process, driven primarily by innate immune cells. Cellular metabolism actively instructs immune signaling and cell fate decisions. Bioenergetic pathways, including glycolysis, mitochondrial respiration, and the tricarboxylic acid cycle, reshape cytokine production and regulate inflammatory cell death pathways. In this review, we synthesize emerging evidence on how metabolic intermediates and pathways regulate inflammasome signaling and the execution of diverse inflammatory cell death modalities, including pyroptosis, necroptosis, PANoptosis, and ferroptosis. We propose that metabolic inputs-including redox balance, mitochondrial dynamics, and lipid modifications-constitute an interconnected metabolic regulatory network that determines the threshold and outcome of inflammatory signaling. This framework offers new insights into immunometabolic dysregulation and therapeutic strategies in inflammatory, infectious, and neoplastic diseases.
The epithelial, microbial, and immune components of the intestinal barrier coexist in harmony to prevent undesirable inflammatory outcomes and ensure homeostasis in the host. In this review, we outline molecular mechanis...The epithelial, microbial, and immune components of the intestinal barrier coexist in harmony to prevent undesirable inflammatory outcomes and ensure homeostasis in the host. In this review, we outline molecular mechanisms by which T cells regulate intestinal homeostasis and how the ageing-associated dysfunction of T cells could disturb host-microbiota symbiosis and the physical integrity of the intestinal barrier, ultimately driving inflammageing and poor health outcomes. Finally, we propose microbiota- and T cell-based therapeutic interventions aimed at strengthening the intestinal barrier to promote healthier longevity. Namely, we discuss the transplantation of youthful microbiota, the use of designed probiotics, and the adoptive transfer of competent or engineered T cells.
While androgen deprivation is widely used in urological oncology to restrain tumor growth and prevent T cell exhaustion, Lee et al. reveal a striking reversal in glioblastoma. In glioblastoma, androgen loss triggers micr...While androgen deprivation is widely used in urological oncology to restrain tumor growth and prevent T cell exhaustion, Lee et al. reveal a striking reversal in glioblastoma. In glioblastoma, androgen loss triggers microglial cytokines, activates the hypothalamic-pituitary-adrenal axis, and induces glucocorticoid-dependent T cell suppression, which accelerates tumor progression.
Bioelectric signaling may represent an emerging layer of macrophage communication. This forum discusses how membrane-potential dynamics, ion fluxes, and context-dependent intercellular coupling may coordinate macrophage...Bioelectric signaling may represent an emerging layer of macrophage communication. This forum discusses how membrane-potential dynamics, ion fluxes, and context-dependent intercellular coupling may coordinate macrophage responses within tissues, highlighting a potential new dimension of immune regulation with broad implications for tissue-level immunity.
Immune-mediated inflammatory disorders, such as inflammatory bowel diseases, are characterized by chronic inflammation and damage to the intestinal barrier. Several of the current therapeutic strategies for inflammatory...Immune-mediated inflammatory disorders, such as inflammatory bowel diseases, are characterized by chronic inflammation and damage to the intestinal barrier. Several of the current therapeutic strategies for inflammatory diseases attempt to decrease inflammation but cause side effects in a significant fraction of patients without promoting remission. Leveraging the power of intestinal regeneration for therapeutic purposes holds great promise, but it comes with the significant risk of promoting tumorigenesis, as most of the pathways that boost the regenerative program are also exploited by tumor cells for their growth and survival. In this article, we review the common mechanisms promoting intestinal regeneration and tumor development and discuss the latest studies identifying cellular and molecular pathways that promote regeneration but not tumorigenesis.
Immunity and metabolism are deeply intertwined in maintaining homeostasis. With the recognition of cytosolic dsDNA sensing as an initiator of immune responses, its interface with metabolic rewiring has emerged as a key a...Immunity and metabolism are deeply intertwined in maintaining homeostasis. With the recognition of cytosolic dsDNA sensing as an initiator of immune responses, its interface with metabolic rewiring has emerged as a key area of investigation. Focusing on the stimulator of interferon genes adaptor protein, critical for dsDNA-mediated inflammation, we examine the link between lipid metabolism and innate immunity. Adopting an evolutionary perspective and through comparisons with the inflammasome pathway, also specialized in innate immune activation, we explore the conservation of this interface across innate immune systems. We propose that the connection between dsDNA sensing and metabolism could unlock innovative precision medicine strategies for inflammatory diseases.
Pancreatic cancer is a deadly disease defined by an immunosuppressive microenvironment refractory to therapy. Kiemen et al. applied 3D histology, imaging mass cytometry, and spatially resolved DNA sequencing to human pan...Pancreatic cancer is a deadly disease defined by an immunosuppressive microenvironment refractory to therapy. Kiemen et al. applied 3D histology, imaging mass cytometry, and spatially resolved DNA sequencing to human pancreata containing early precursors of the disease, revealing heterogeneous and mutation-specific inflammatory niches that are poorly resolved by 2D methods.
Tissue-resident macrophages exhibit remarkable plasticity, dynamically adapting to their local environment and adopting tissue-specific phenotypes that support organ homeostasis. The underlying identity-determining trans...Tissue-resident macrophages exhibit remarkable plasticity, dynamically adapting to their local environment and adopting tissue-specific phenotypes that support organ homeostasis. The underlying identity-determining transcriptional programs are instructed by microenvironmental cues. Transforming growth factor-β (TGF-β), which has long been recognized for its role in immunosuppression, has recently emerged as a pivotal determinant of tissue macrophage identity. In this review, we highlight how TGF-β shapes innate immunity by driving macrophage imprinting and transcriptional programming within defined tissue niches. We emphasize that the spatial and temporal regulation of TGF-β activation-rather than its overall abundance-governs its divergent effects on immune cells. Understanding the precise mechanisms promises to spur the development of more selective therapeutic strategies for modulating macrophage function in health and disease.
Neutrophil asthma is a severe, corticosteroid-resistant subtype characterized by airway neutrophilia and declining lung function. Su et al. identify a sirtuin 6-lactate dehydrogenase A-histone lactylation axis that links...Neutrophil asthma is a severe, corticosteroid-resistant subtype characterized by airway neutrophilia and declining lung function. Su et al. identify a sirtuin 6-lactate dehydrogenase A-histone lactylation axis that links macrophage glycolysis to epigenetic chemokine regulation, offering mechanistic insight into neutrophil recruitment and highlighting potential therapeutic targets.
Ridelfi M, Zucconi Galli Fonseca V, Sala C
… +1 more, Rappuoli R
Trends Immunol
· 2026 May · PMID 42203543
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Antimicrobial resistance (AMR) is one of today's most worrisome health emergencies. Bacteria, once easily treatable with antibiotics, have acquired resistance to many or all available drugs. In 2019, 1.27 million infecti...Antimicrobial resistance (AMR) is one of today's most worrisome health emergencies. Bacteria, once easily treatable with antibiotics, have acquired resistance to many or all available drugs. In 2019, 1.27 million infection-related deaths were directly caused by AMR. By 2050, AMR could put 10 million lives per year at risk, particularly in low- and middle-income countries. This review focuses on monoclonal antibodies (mAbs) as a novel class of antimicrobials that can bypass classical resistance mechanisms and exert prophylactic and therapeutic effects. The advantages and limitations of mAbs are discussed, along with the need for rapid diagnostics for personalized use. The risk of selecting resistant strains is also addressed, as well as strategies to reduce production costs, expand global access, and improve equity.