Respiratory immunology: an ancient yet emerging interdisciplinary field

Respiratory immunology: ancient roots, emerging field

The lung is among the organs most continuously exposed to the external environment. With every breath, the respiratory tract encounters pathogens, allergens, particulate matter, tobacco smoke, industrial pollutants, and other airborne stimuli. It must therefore function not only as an organ of gas exchange, but also as a highly specialized barrier surface that integrates immune surveillance, inflammatory control, epithelial protection, and tissue repair.^1,2 Tissue-resident immune cells, epithelial cells, stromal cells, and soluble mediators together maintain a dynamic equilibrium between host defense and immune tolerance at this environmental interface.^3,4 An effective respiratory immune response must be rapid enough to eliminate threats, sufficiently restrained to protect the alveolar–capillary barrier, and flexible enough to restore tissue integrity after injury. When this balance fails, the consequences may manifest as infection, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, lung cancer, or acute inflammatory lung injury.^4,5

A growing recognition is reshaping our understanding of respiratory disease: the clinical course of many lung diseases is determined not only by the initiating pathogen, allergen, pollutant, tumor, or fibrotic stimulus, but also by the host immune response that unfolds within the respiratory microenvironment. The same viral infection may resolve uneventfully in one patient but progress to severe pneumonia or acute respiratory distress syndrome in another. The same epithelial injury may be repaired in one individual yet evolve into chronic fibrosis in another. These divergent outcomes cannot be fully explained by organ-level pathology alone. They point instead to immune balance, epithelial and immune cell states, spatial niches, and tissue repair programs as central determinants of disease trajectory.5, 6, 7, 8 These clinical observations, made across infections, asthma, fibrosis, and cancer, share a common immunological thread that has taken decades to recognize explicitly.

This is why respiratory immunology deserves renewed attention. The field is ancient in its questions but young in its investigative power. For centuries, clinicians have recognized respiratory manifestations including cough, sputum production, wheezing, hemoptysis, dyspnea, and fever, while pathological and imaging studies have characterized structural abnormalities such as consolidation, cavitation, and scarring. Although these phenomena were not originally described in immunological terms, they reflected host defense, inflammation, tolerance, tissue damage, and repair. Classical diseases such as tuberculosis already illustrate that respiratory disease progression depends on the interplay among pathogen persistence, cellular immunity, granuloma formation, immune evasion, and tissue destruction.^9,10 Today, new technologies allow these longstanding clinical problems to be revisited directly in human lung tissues and at unprecedented resolution. Respiratory immunology is therefore no longer merely the application of immunology to pulmonary disease. Instead, it views the lung as a unique immune-ecological organ in which barrier defense, immune tolerance, tissue repair, regeneration, metabolism, and environmental sensing are dynamically integrated.^1,2,4,5 Traditional inflammation-centered models are gradually being replaced by multicellular immune ecosystem models that capture dynamic immune-state trajectories and the spatial organization of cells.^7,11 Respiratory immunology is emerging as an independent interdisciplinary framework with its own central question: how does the lung preserve both host defense and gas exchange while limiting immune-mediated injury under continuous environmental exposure?

From inflammation to immune microenvironments

The historical depth of respiratory immunology is most evident in infectious lung disease. Tuberculosis illustrates that disease outcomes depend not only on pathogen persistence, but also on the balance among immune activation, tissue injury, and repair.^9,10 These immune–injury–repair states are spatially organized within diseased lung tissue, and spatial mapping of immune cell niches may reveal hyperinflammatory or reparative microenvironments, potentially informing timely intervention.^7,11,12 A similar principle applies to severe viral pneumonia, in which pathogen load and host immunity interact to determine whether tissue repair succeeds or progresses toward excessive damage. In both settings, identifying activated immune populations within defined anatomical compartments can inform clinical management and support targeted therapeutic strategies.^1,5,11,12

The same perspective is reshaping the understanding of noninfectious respiratory diseases. Asthma and chronic obstructive pulmonary disease (COPD) are increasingly interpreted through epithelial barrier dysfunction and immune-inflammatory endotypes, rather than airflow limitation alone.^5,13 Profiling immune endotypes and epithelial integrity can guide biologic or anti-inflammatory strategies by linking immune state, tissue injury, and repair to therapeutic decision-making. For example, single-cell spatial transcriptomic analysis of endobronchial biopsies has revealed discrete epithelial–stromal–immune niches in the asthmatic airway wall, while molecular profiling of airway epithelial samples and bronchial biopsy specimens has identified type 2-high phenotypes associated with corticosteroid responsiveness and potential sensitivity to therapies targeting type 2 cytokine pathways.^14,15 In COPD, spatial proteomic and transcriptomic profiling has identified emphysema-associated lymphoid follicles characterized by aberrant chronic B-cell activation, providing a potential molecular basis for disease stratification.¹⁶ These examples show how high-resolution spatial and molecular mapping may inform patient stratification and precision therapy. Pulmonary fibrosis is no longer viewed simply as excessive collagen deposition, but as a chronic failure of epithelial repair involving alveolar type 2 cell dysfunction, macrophage-state changes, immune–stromal crosstalk, fibroblast expansion, and persistent remodeling.6, 7, 8 Monitoring these immune–stromal interactions helps identify windows for antifibrotic or regenerative intervention, integrating immune, inflammatory, injury, and repair dynamics into precision strategies.^7,8,11 Lung cancer therapy has also entered an immunological era, in which immune checkpoint signaling, myeloid immunosuppression, T-cell exhaustion, tumor-associated macrophage programs, metabolic restriction, and antigen heterogeneity collectively shape responses to therapy.¹⁷ Assessing spatial immune niches together with the tissue injury–repair context may further optimize immunotherapy and patient stratification.^11,17 Together, these reconceptualizations have created an intellectual demand for tools capable of resolving cellular heterogeneity, spatial organization, and multicellular interactions in human tissue.^7,11,12

This conceptual shift has been accelerated by technological advances. For a long time, respiratory immunology relied on histopathology, bronchoalveolar lavage, peripheral blood assays, animal models, and selected molecular markers. These approaches remain essential, but they are often insufficient for identifying the origin, state, location, and interactions of cells that drive injury, repair, or chronic remodeling.¹² Single-cell RNA sequencing has revealed immune, epithelial, endothelial, and stromal heterogeneity across healthy and diseased lungs.^6,11 These technologies not only provide high-resolution cellular profiling, but also reveal that diseases such as asthma, COPD, pulmonary fibrosis, and lung cancer are driven by dynamic multicellular interactions rather than by discrete pathological processes acting in isolation. By mapping immune, epithelial, and stromal cell interactions, single-cell and spatial omics approaches uncover dynamic pathogenic mechanisms that can inform precision interventions.^11,12 Spatial transcriptomics, multiplex imaging, and spatial proteomics now connect cell states to tissue architecture, allowing investigators to ask where pathological interactions occur, which niches expand during disease, and how immune networks differ among injury, repair, and chronic remodeling.^7,11

The key gain is not technical novelty for its own sake. The real advance lies in a change in reasoning. We can now move beyond asking whether inflammation is increased to asking which cell populations are activated, in which anatomical compartments, at which disease stage, through which ligand–receptor interactions, and with what consequences for barrier integrity and tissue repair.^7,11,12 In pulmonary fibrosis, for instance, spatial and single-cell analyses have begun to define pathological niches that include injured epithelium, transitional epithelial states, pro-fibrotic macrophages, activated fibroblasts, altered endothelium, and abnormal extracellular matrix organization.^7,8 These findings explain why simple anti-inflammatory strategies are often inadequate: the pathological unit is not a single cytokine, but an evolving multicellular microenvironment.

Human-centered models are equally important. Integrated single-cell and multi-omic approaches are helping to bridge the gap between experimental mechanisms and human disease biology.^11,12 Integrated computational approaches facilitate the analysis of single-cell, spatial, proteomic, imaging, and clinical datasets.^11,12 Artificial intelligence can further support the analysis of complex multimodal respiratory data, including imaging data, physiological measurements, longitudinal monitoring data, and other clinical information.¹⁸ Together, these approaches are transforming respiratory immunology from a descriptive field into a systems-level discipline capable of mapping disease trajectories and identifying windows for intervention.^11,12,18

Toward precision respiratory immunology

The practical implication is clear: future respiratory medicine should not classify diseases solely by symptoms, radiological findings, spirometry, histology, or pathogen identity. It should also classify them according to immune state, tissue niche, repair capacity, and therapeutic vulnerability.^7,12 In ARDS, identifying biologically distinct inflammatory phenotypes may support patient stratification and inform the evaluation of targeted or supportive interventions.^19,20 In CTD-ILD, integrating immune-cell states with fibrotic and tissue-repair programs may improve mechanistic classification and therapeutic stratification.^21,22 This does not mean replacing established clinical categories; rather, it means enriching them with mechanistic information that can guide patient stratification, biomarker discovery, and precision intervention.^11,12 Across diseases, these examples show that incorporating immune microenvironments and tissue repair dynamics into disease evaluation is critical for precision strategies, even without exhaustive mechanistic dissection in every context.^7,11,12 Fig. 1 provides a conceptual overview linking immune state, inflammation, tissue injury and repair across the diseases discussed.

Fig. 1.

Shared immune–inflammation–injury dynamics across major respiratory diseases. Despite distinct clinical manifestations, major respiratory diseases converge on shared processes involving immune barrier dysfunction, inflammation, and tissue injury. The extent and persistence of dysregulation across these processes shape divergent disease trajectories. A resolving/reparative trajectory promotes tissue repair, regeneration, and restoration of homeostasis, whereas a persistent/progressive trajectory sustains immune dysregulation, inflammation, and tissue injury, ultimately driving chronic remodeling, fibrosis, functional impairment, or disease progression. The surrounding panels illustrate representative disease-specific manifestations of this shared framework. ARDS, Acute respiratory distress syndrome; COPD, Chronic obstructive pulmonary disease; CTD-associated ILD, Connective tissue disease-associated interstitial lung disease.

Several priorities deserve emphasis, and they can be considered at two interconnected levels. At the scientific level, respiratory immunology should remain anchored in human disease. Animal models are indispensable, but the field should increasingly validate mechanisms in human lung tissues, bronchoalveolar lavage, clinical cohorts, and spatially resolved pathology.^11,12 Equally important, the field should focus on dynamics rather than static snapshots. The same immune pathway may be protective during early host defense, harmful during uncontrolled inflammation, and reparative during recovery.^1,3 Timing, location, and cellular context must therefore be incorporated into experimental design and therapeutic development.^5,7

At the translational level, intervention strategies should move beyond broad immune suppression. The next stage will require precise modulation of immune states, epithelial–immune crosstalk, macrophage programs, stromal activation, and repair-associated niches.^5,7,8 Advances in antibody-based therapy and immune-cell engineering, including CAR-T approaches, may enable more precise intervention at defined tissue sites and disease stages.²³ This is particularly relevant for chronic respiratory diseases, in which therapeutic efficacy depends on restoring tissue homeostasis rather than merely blocking inflammation.^6,8

Despite these technological advances, translating integrated platforms into routine clinical practice remains challenging. Single-cell RNA sequencing requires high-quality fresh tissue, which is often difficult to obtain from patients, and spatial transcriptomics depends on precise tissue processing and preservation.^11,12 Artificial intelligence (AI)-based analyses require large, well-annotated datasets that are rarely available in typical clinical settings. Moreover, high costs, technical complexity, and the lack of standardized protocols hinder widespread adoption.^11,12,18 Bridging this gap will require standardization of sample preparation and analytical workflows, validation of findings in human cohorts, and closer collaboration among clinicians, computational scientists, and translational researchers to ensure that emerging insights can inform patient care.^11,12

This translational shift will require deeper collaboration. Pulmonologists bring the clinical questions; immunologists provide mechanistic frameworks; pathologists and imaging scientists reveal tissue organization; computational biologists integrate high-dimensional data; and materials scientists and pharmacologists design targeted delivery systems.^11,12 Accelerating this interdisciplinary convergence is, in our view, one of the most consequential tasks for the field in the coming decade.

Respiratory immunology has reached a point at which old clinical questions can be addressed with new spatial and molecular precision.^7,11 Its future value will depend on whether high-resolution spatial and molecular maps can be converted, with the aid of computational and AI-based modeling, into testable mechanisms, clinically useful biomarkers, and safer, more precise interventions.^12,18 For investigators and clinicians in respiratory medicine, the central challenge is no longer simply to characterize discrete immune, stromal, or epithelial changes, but to understand how immune–stromal–parenchymal interactions determine disease fate—and how they can be therapeutically redirected. For China’s growing respiratory research community, and for the broader international field, this is also an opportunity to build integrated platforms that combine clinical cohorts, spatial pathology, multi-omics, and AI-based computational modeling. More broadly, respiratory immunology is emerging as a unifying framework for understanding lung disease biology across infection, inflammation, fibrosis, and cancer. By integrating immune microenvironments, spatial cellular organization, and tissue repair programs, this perspective shifts the focus from static organ-level pathology to dynamic multicellular ecosystems, providing a conceptual roadmap for future precision interventions and research directions.

CRediT authorship contribution statement

Yuqing Lv: Writing – original draft, Visualization, Investigation, Conceptualization. Weining Xiong: Writing – review & editing, Visualization, Conceptualization. Bin Cao: Writing – review & editing, Supervision, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Edited by: Peifang Wei