Cellular senescence is a stress-response program that coordinates cell-autonomous growth arrest and non-cell autonomous remodeling of the tissue environment. Initially defined through its role in aging and tumor suppression, senescence is now recognized as a highly complex program shaped by cell-intrinsic and environmental factors. This complexity places senescence as a broad stress response mechanism operating at the intersection of metabolic dysfunction, chronic inflammation and tissue repair. Given its constant exposure to metabolic, inflammatory and toxic stress alongside its high regenerative demands, the liver is particularly prone to engage senescence as a protective mechanism to maintain tissue integrity. In this context, senescence exerts dual and often opposing effects. This review discusses the multifaceted roles of senescence along the liver disease trajectory, from its early protective functions in tissue repair to its later pathologic contributions to chronic liver disease and tumor progression, underscoring how cell type, stage of senescence program, disease stage and microenvironmental cues shape these divergent outcomes. We highlight the potential of emerging therapeutic interventions that modulate senescence, including pro-senescence, senolytic, senomorphic, and immune-modulating strategies. Advancing our understanding of the multifaceted roles of cellular senescence will be essential to translate this knowledge into therapies that selectively modulate senescent cell states, harnessing their beneficial effects while limiting their detrimental roles in chronic liver disease and cancer.
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health challenge and the leading cause of death from a single infectious agent. Despite diagnostic and therapeutic advances, the COVID-19 pandemic reversed progress in TB control, with a notable rise in incidence across Latin America. This region bears a disproportionate burden of the disease due to socioeconomic inequality, limited access to healthcare, and high rates of multidrug-resistant TB. Interactions among pathogen genetics, host susceptibility, immune response, and environmental determinants critically shape disease outcomes. Several key questions remain about the higher incidence of TB in the Americas, including the roles of genetic predisposition, environmental factors, and social determinants such as poverty and migration. Addressing these issues is essential to refining control strategies. Accordingly, this review provides an updated overview of TB in Latin America, integrating immunological, genetic, and socio-epidemiological perspectives that could be useful for future research and policy discussions toward more region-specific interventions against Mtb.
Inflammation is a pathogenetic driver of several pathological conditions, including cancer. The tumor microenvironment, which includes cellular, molecular, and structural components, is an essential component of cancer, involved in tumor promoting or controlling processes. In particular, inflammatory players contribute to the establishment of a tumor-promoting microenvironment, which affects all stages of tumor development, from initiation to metastasis, as well as response to therapy. The IL-1 system includes two large sets of structurally related ligands and receptors, with agonist or regulatory activity, playing non-redundant roles in inflammation and immunity. Each of them has specific functions in tissue homeostasis, inflammation, innate and adaptive immune responses, and potentially contributes to processes related to carcinogenesis and metastasis, or immune-mediated control of cancer cells. Depending on the context and cellular target, IL-1 family members may play dual roles in cancer, driving both pro- or anti-tumor processes. IL-1α and IL-1β can directly promote cancer cell proliferation, survival, and plasticity, in addition to contribute to the establishment of a pro-inflammatory environment that promotes tissue remodeling, cellular stress responses, and genomic instability. On the other hand, IL-1 is a lymphoproliferative and activating molecule in innate and adaptive responses, thus contributing to anti-tumor immune mediated responses. In addition, members of the IL-1 system act as regulators of mechanisms involved in cancer, including emergency hematopoiesis, trained immunity, and metabolism. Here, we will provide an overview of the IL-1 system in cancer and discuss the functional complexity of IL-1 family cytokines, which orchestrate both protective and pro-tumorigenic responses, by directly acting on cancer cells and by driving environmental stimuli which indirectly act on cancer cells.
Inflammation is a fundamental immune response that protects against injury and infection; however, when unresolved, it can contribute to disease pathogenesis. Chronic inflammation is a hallmark of cancer that promotes tumour initiation and metastatic spread. Notably, this relationship is bidirectional: while chronic inflammation can promote tumour initiation, tumours themselves actively drive systemic inflammation. Two related members of the interleukin-1 (IL-1) family, IL-1α and IL-1β, are pleiotropic cytokines that link local tumour activity to systemic immune dysregulation and have emerged as principal drivers of this process. Tumour-derived IL-1β reshapes haematopoiesis in the bone marrow, promoting myeloid-skewed output and the expansion and polarisation of monocytes and neutrophils. These tumour-educated myeloid cells actively contribute to disease progression and metastatic spread through a range of mechanisms including suppression of anti-tumour immunity. In this review, we synthesise the current understanding of how tumours induce IL-1 production and how IL-1-driven systemic inflammation remodels the tumour macro-environment. We highlight emerging evidence that myeloid cell reprogramming occurs in a layered process, proposing a model of hierarchical myeloid education across the bone marrow and peripheral tissues and outline the therapeutic potential of targeting IL-1 signalling to disrupt tumour-promoting inflammation.
Interleukin-1β (IL-1β) has long been characterized as a foundational mediator of innate immunity, yet this designation captures only a fraction of its biological significance. A growing body of evidence now positions IL-1β as a molecular arbiter of tissue restoration - a context-sensitive instructor that orchestrates the dynamic interplay between inflammatory signaling, stem cell fate, and niche remodeling that collectively determines whether an injured tissue regenerates or degenerates. Far beyond its canonical role in host defense, IL-1β functions as a critical regulator of cell state plasticity, driving the transition of lineage-committed progenitors into highly plastic, transitional identities that are indispensable for effective wound repair. Yet the very mechanisms that render IL-1β essential for regeneration also render it capable of profound pathological consequence when its activity is sustained, amplified, or spatiotemporally dysregulated. This review explores the spatiotemporal logic governing IL-1β-mediated plasticity, with particular emphasis on the respiratory epithelium as a primary and instructive model of inflammatory reprogramming and niche remodeling. We examine how the signaling thresholds, cellular contexts, and temporal dynamics of IL-1β activity collectively determine regenerative outcomes - and how the failure to terminate this program pathologically stabilizes transitional progenitor states, predisposing tissues to fibrosis, functional exhaustion, and malignant transformation. By integrating evidence spanning transcriptional, epigenetic, and metabolic rewiring, we propose a unified conceptual framework for understanding IL-1β as a master coordinator of the regenerative ecosystem - one whose precise modulation represents a compelling therapeutic target for resetting pathological cell states toward functional recovery in chronic inflammatory diseases.
Ferroptosis links cellular metabolism to immune regulation. Beyond its role as an iron-dependent form of regulated cell death, ferroptosis generates signals, including oxidized lipids, iron metabolites, and damage-associated molecular patterns, that influence inflammatory and immune responses. The pancreas is particularly susceptible to ferroptotic stress because of its high metabolic demand and close integration with immune and stromal networks. In pancreatitis, ferroptosis translates metabolic injury into innate immune activation, contributing to sterile inflammation and tissue damage. In pancreatic cancer, ferroptotic vulnerabilities can be exploited therapeutically, yet ferroptosis-associated signals may also support immune suppression, immune evasion, and treatment resistance. These findings suggest that ferroptosis functions as an immunometabolic checkpoint rather than simply a cell death program. Here, we discuss how ferroptosis shapes immune responses in pancreatitis and pancreatic cancer and examine the factors that determine whether it promotes inflammation, antitumor immunity, or immune tolerance. We also review ferroptosis-targeted therapies and the challenges associated with their clinical application.
Inflammation is a defining feature of the tumor microenvironment (TME) and a key driver of cancer progression. Among inflammatory mediators, the interleukin-1 (IL-1) family of cytokines serves as a central mediator linking tissue damage, metabolic stress and microbial cues to innate immune activation. Myeloid cells are major components of this network, with macrophages and neutrophils acting both as highly responsive targets of IL-1 family signaling and as important sources of IL-1 family cytokines, thereby establishing self-reinforcing inflammatory loops within tumors. Recent advances in single-cell and spatial analyses have revealed the remarkable heterogeneity of tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs), highlighting how IL-1 family cytokines shape their recruitment, differentiation, and functional reprogramming in cancer. In turn, myeloid-derived IL-1 family cytokines contribute to inflammatory networks that influence tumor growth, immune suppression, and stromal remodeling. Here, we review the reciprocal interactions between IL-1 family cytokines/receptors and myeloid cells in cancer, focusing on how IL-1 family members instruct macrophage and neutrophil responses and how these cells shape IL-1 family-driven inflammatory circuits in the TME.
Interleukin-1 (IL-1) exerts a pivotal role in the regulation of innate immune responses and inflammatory processes. Beyond its local effects at the site of inflammation, IL-1 acts as a systemic regulator of hematopoiesis by reprogramming hematopoietic stem and progenitor cells (HSPCs), thereby shaping the functional properties of the myeloid progeny. Through induction of emergency myelopoiesis and inflammatory memory, IL-1 can imprint durable epigenetic, metabolic and transcriptomic changes within the hematopoietic compartment, altering immune output well beyond the initial inflammatory trigger. This systemic effect of IL-1 signaling is particularly relevant in the context of cancer, since tumors are now viewed as inflammatory entities providing persistent inflammatory factors that can influence hematopoiesis and imprint an immunosuppressive phenotype in myeloid cells. In parallel, aging and clonal hematopoiesis (CH) are characterized by chronic low-grade inflammation in which IL-1 signaling may amplify mutant progenitor expansion, linking inflammaging to increased susceptibility to both hematological malignancies and solid cancers. Here, we discuss the role of IL-1 signaling in emergency myelopoiesis and both central and peripheral inflammatory memory, and how these processes shape cancer progression. We also highlight the therapeutic potential of targeting IL-1-mediated hematopoietic reprogramming.
Stress, a prevalent factor in modern life, profoundly impacts human health by disrupting immune function and intestinal homeostasis. This review elucidates the mechanisms through which stress dysregulates the hypothalamic-pituitary-adrenal (HPA) and sympathetic-adrenal medulla (SAM) axes, leading to altered glucocorticoid and catecholamine levels that impair immune responses and promote inflammation. Chronic stress exacerbates gut microbiota dysbiosis, reduces microbial diversity, and compromises intestinal barrier integrity, contributing to conditions like inflammatory bowel disease (IBD). Stress-induced HPA axis dysfunction and neuroendocrine alterations further aggravate IBD pathogenesis by enhancing pro-inflammatory pathways (e.g., IL-6/STAT3) and disrupting mucosal immunity. Clinical evidence highlights bidirectional links between psychological stress and IBD progression, with stress exacerbating symptoms and IBD increasing susceptibility to anxiety and depression. Therapeutic strategies, including probiotics, anti-inflammatory agents, and psychological interventions (e.g., yoga), show promise in mitigating stress-related gut inflammation and improving patient outcomes. This synthesis underscores the necessity of integrating psychological care with conventional treatments to address the multifaceted interplay between stress, immunity, and gut health in IBD management.
Dendritic cells (DCs), the most proficient antigen-presenting cells, bridge innate and adaptive immunity and are critical for anti-cancer immune surveillance. Their function is precisely regulated by protein tyrosine kinases (PTKs), which integrate signals from external stimuli and internal cellular stress to control DC maturation, migration, and antigen presentation. This review systematically synthesizes current knowledge on PTK roles in DC-mediated anti-tumor immunity, with a focused analysis of their differential expression and function across human and mouse DC subsets-including conventional (cDC1, cDC2), plasmacytoid (pDC), and monocyte-derived DCs. We highlight how specific PTK families (e.g., TAM, PDGFR, SRC, JAK) translate pathogen- and damage-associated signals into tailored immune responses. Furthermore, we discuss the dual impact of clinically approved PTK inhibitors on DC function, which can either enhance or suppress anti-tumor immunity depending on context. Finally, we evaluate translational strategies that combine PTK-targeted agents with DC-based vaccines or immune checkpoint blockade, offering a rationale for exploiting PTK-DC crosstalk to develop more effective combinatorial immunotherapies.
Latin America and the Caribbean host one of the world's most complex intersections of ancestry, pathogen exposure, and environmental change, generating an immunological landscape that cannot be fully understood through frameworks derived from high-income regions. The region's immune profiles reflect the legacy of colonization, population collapse, forced migration and admixture, together with more recent transformations driven by urbanization, dietary change, pollution and shifts in microbial exposure. These factors contribute to variability in immune responsiveness, susceptibility to infection and immune mediated and metabolic diseases. In this review, we aim to integrate insights from population genomics, infectious disease epidemiology, environmental immunology and social determinants of health to examine how these processes contribute to immune variation across LAC. We highlight how ancestry associated immunogenetic variation, in interaction with environmental and socioeconomic context, may contribute to heterogeneity in host-pathogen interactions, inflammation regulation and vaccine responses. We further discuss how persistent infectious exposures coexist with rising non-communicable diseases, generating distinct immunological trajectories. Understanding immunity in LAC may provide a framework for developing context specific interventions while offering broader insight into how ancestry, environment and social conditions shape human immune adaptation.
Lymphocytes B cells (B cells) play a determinant role in the pathogenesis of type 1 diabetes (T1D); indeed, B cells antigen-presentation capabilities are largely described as a main contributing pathogenic factor. Recent evidences highlighted the role of islet antigen-reactive B cells as a perpetuated contributor to autoantibodies seroconversion and the progression to the late stages of the disease. A loss of B cells anergy towards islet-specific antigens, can be recognized in T1D. Aside from their well characterized role during the pathogenesis and early onset of T1D, a fundamental regulatory role of a subset of B cells, namely regulatory B cells, has proven its relevance in the time course of the disease. Since targeting B cells showed little or no additional benefits; instead, harnessing strategies to expand B regulatory cells could represent an attractive therapeutic path to tackle inflammation and curb diabetes.
Oncolytic virotherapy emerged as a revolutionary approach to immunotherapy in cancer treatment. Newcastle disease virus (NDV), a promising oncolytic agent of the Paramyxoviridae family, has gained considerable attention as an immunotherapeutic agent against cancer mainly due to its inherent tumor selectivity, broad tropism, convenient propagation, and lack of pre-existing immunity in humans. Its selective tropism is primarily mediated by an impaired type I interferon signalling pathway in cancer cells. Apart from the direct lysis, NDV induces immunogenic cell death (ICD), releasing tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs), which in turn lead to potent activation of innate and acquired immunity. The efficiency of the wild-type NDV strains has been improved through genetic engineering. Recombinant strains capable of expressing immuno-stimulatory cytokines and enzymes to remodel the immuno-suppressive tumor microenvironment (TME) are the most promising. This review discusses the history of early events that shaped NDV into an 'oncolytic agent'. It reviews its characteristics and mechanisms of anti-tumor activity, which can directly or indirectly form part of the cancer immunity cycle. Further, limitations and issues surrounding the unmet translational delay of NDV as an immuno-therapeutic agent in personalized and combination immunotherapy strategies are also discussed.
The interleukin-1 (IL-1) superfamily encompasses a group of cytokines with central roles in inflammation and immune regulation. IL-1 is directly implicated in activating survival and proliferative pathways in transformed cells, orchestrating the angiogenic switch, remodeling the extracellular matrix, and driving invasion and metastatic colonization. Here we review the diverse cellular sources of IL-1, spanning from monocytes to non-immune cell types such as cancer cells, stromal fibroblasts, and endothelial cells. We also discuss IL-1-neutralizing strategies, including monoclonal antibodies, decoy receptors, and competitive receptor antagonists, currently or previously tested in clinical trials, with particular attention to the most recent and unsuccessful combinations, notably with immune checkpoint inhibitors. Finally, we highlight emerging evidence linking IL-1 axis to resistance against Epidermal Growth Factor Receptor (EGFR)-targeted therapies. Together, these findings suggest that targeting the IL-1 axis in combination with EGFR-TKIs could impair tumor initiation and relapse and mitigate inflammation-driven therapeutic escape, offering a promising avenue for future clinical development.
Chagas disease, caused by Trypanosoma cruzi, remains one of the most striking examples of how parasite genetic diversity and host immune heterogeneity converge to shape chronic infection outcomes. This review integrates findings from studies across Latin America -Mexico and Central America, the Andean countries, Brazil, and Argentina - to reveal both shared and region-specific features of T-cell response and cytokine immune regulation in chronic infection. Across regions, disease progression reflects the balance between proinflammatory and regulatory networks: effective parasite control depends on IFN-γ- and TNF-α-driven Th1 and cytotoxic responses, yet persistent activation and insufficient counter-regulation by IL-10, TGF-β, and regulatory lymphocytes lead to immune dysregulation, inflammation, and fibrosis. IND patients maintain polyfunctional and IL-10-modulated T-cell responses, whereas patients with cardiomyopathy display monofunctional, exhausted effector cells expressing inhibitory receptors such as PD-1, CTLA-4, and TIM-3. Distinct cytokine profiles and immune-checkpoint dynamics observed among populations likely reflect differences in host genetics, immune background, and parasite diversity across the continent. Together, these findings outline a continuum of immune regulation in human Chagas disease and emphasize that restoring the equilibrium between effector and regulatory pathways - rather than amplifying one over the other - will be key for developing future immunomodulatory therapies and vaccines. Further understanding how parasite lineage, host genetics, and environmental context shape T-cell and cytokine networks is essential to develop regionally tailored immunotherapies and vaccines capable of restoring immune homeostasis without exacerbating pathology and, importantly, instruct strategies that can be used in all regions.
The COVID-19 pandemic had a profound impact on Latin America, exposing structural inequalities, fragmented healthcare systems, and longstanding technological dependence. The region experienced a high burden of infection and excess mortality, influenced by socioeconomic vulnerability and a high prevalence of metabolic comorbidities. In response, countries expanded diagnostic capacity, strengthened genomic surveillance, and increased participation in clinical research and therapeutic evaluation. Coordinated regional collaboration facilitated the detection and tracking of emerging SARS-CoV-2 variants. Local innovation also advanced diagnostic platforms and vaccine development, leading to regionally produced vaccines such as Soberana, Abdala, ARVAC, and Patria. These initiatives generated valuable clinical and immunological data, including characterization of inflammatory biomarkers associated with severe disease and evidence of hybrid immunity in highly exposed populations. However, persistent inequities in healthcare access, research investment, and manufacturing capacity continue to constrain regional self-sufficiency. Although collaboration among academia, industry, and government reduced certain external dependencies, structural limitations in funding stability, regulatory harmonization, and large-scale production remain. The Latin American experience highlights both adaptive scientific capacity during crisis conditions and the challenges of consolidating emergency-driven advances into durable preparedness. Sustained investment and coordinated governance will likely determine whether short-term responsiveness translates into long-term regional strengthening.
