Immunological mechanisms and therapeutic approaches in pulmonary fibrosis

Abstract

Pulmonary fibrosis (PF), the irreversible scarring of the lungs in many interstitial lung diseases, remains fatal despite currently approved antifibrotic therapy. Converging evidence shows that dysregulated innate and adaptive immunity orchestrates every stage of the fibrotic cascade. Roughly 20% of PF susceptibility loci map to immune regulatory genes, including Toll-interacting protein, interleukin (IL)-1 receptor antagonist, Toll-like receptor-3, complement receptor-1 and tumour necrosis factor-α (TNF-α), indicating that genetically primed host defence pathways predispose to maladaptive repair. Recurrent epithelial injury triggers a type 1 inflammatory response that gradually shifts toward type 2-skewed wound healing; the resulting cytokine milieu rich in transforming growth factor-β, IL-13, IL-6 and platelet-derived growth factor reprogrammes fibroblasts into collagen-secreting myofibroblasts. Spatial-omic profiling of PF lungs corroborates this model, revealing niches where profibrotic macrophages, T-helper cells and inflammatory fibroblasts colocalise within a stiff, collagen-rich matrix. Beyond their direct antimesenchymal actions, the current therapeutics pirfenidone and nintedanib also temper innate and adaptive immune signalling. Proof of concept for sharper immunomodulation now comes from recent phase III trials of nerandomilast, a highly selective phosphodiesterase-4B inhibitor that preserved forced vital capacity and downregulated TNF-α, IL-6 and IL-17 networks. These results demonstrate that immune pathway modulation can complement existing antifibrotics and invigorate efforts to align mechanism-based therapies with patient-specific immune endotypes, steered by genetics, cellular phenotypes and circulating biomarkers. This review synthesises current understanding of how immunity initiates, amplifies and perpetuates PF, linking genetic and mechanistic insights to emerging therapeutic opportunities. A deeper grasp of immune–epithelial–fibroblast crosstalk is essential for transforming disease-slowing care into genuinely disease-modifying intervention.

Shareable abstract

The immune system contributes to pulmonary fibrosis as both an initiator and amplifier. Antifibrotics remain the foundation of care, but emerging evidence suggests endotype-guided immunomodulation could transform treatment into disease-modifying therapy. https://bit.ly/3YElINQ

Introduction

Interstitial lung diseases (ILDs) encompass a heterogeneous family of disorders in which inflammation or scarring of the pulmonary interstitium progressively compromises gas exchange and leads to breathlessness, exercise limitation and impaired quality of life [1, 2]. Although many ILDs follow an indolent course, a sizeable subset, collectively referred to as progressive pulmonary fibrosis (PPF), is characterised by relentless decline in lung function and high mortality despite current therapy [2, 3] (figure 1). Idiopathic pulmonary fibrosis (IPF) is not included in the clinical definition of progressive pulmonary fibrosis (PPF), yet biologically it remains the archetypal form of relentlessly progressive fibrotic ILD and has shaped our understanding of fibrotic disease mechanisms. It typically affects men over 50 years of age, is intrinsically progressive from the outset and carries a median transplant-free survival of only 2–3 years when not treated [4]. Pulmonary fibrosis (PF) is now understood to be the pathological end-result of a maladaptive wound healing response that unfolds at the interface of three cellular compartments, namely the epithelium, the immune system and the mesenchyme. Repetitive injury to alveolar type-II (AT2) cells by environmental toxins, chronic infection or autoimmune attack, triggers the release of danger-associated molecular patterns (DAMPs) that can mobilise innate and adaptive immune cells [5]. In healthy lungs, this inflammatory phase resolves, but in PF persistent immune activation may sustain the production of profibrotic mediators, likely contributing to fibroblast activation, myofibroblast accumulation and excessive extracellular matrix (ECM) deposition [6]. Fibrotic lung tissue shows aggregates of immune cells within fibrotic foci [7, 8]. Increased levels of inflammatory cytokines in broncho-alveolar lavage fluid (BALF) correlate with decline in forced vital capacity (FVC) or survival [9–12]. Post mortem analyses confirm that these immune signatures persist into end-stage disease, indicating that inflammation is not merely an early event but a continual amplifier of fibrosis [13].

FIGURE 1.

Interstitial lung disease (ILD) subtype classification and percentages leading to progressive pulmonary fibrosis (PPF). ILDs can be classified into several subtypes, including auto-immune related, exposure-related, mixed group of (ultra) rare diseases, sarcoidosis and idiopathic interstitial pneumonia (IIP). Bar graphs indicate the proportion of patients in each ILD-subgroup that develops into PPF [2–4, 13]. Of note, idiopathic pulmonary fibrosis (IPF) is regarded as a separate entity, as IPF does not develop into PPF, but is a progressive fibrotic disease in itself. Furthermore, the estimated % of sarcoidosis patients of ILD (30%) is based on expert ILD centre cohorts. Expert ILD centres see a disproportionate number of fibrotic and complex ILDs, while many sarcoidosis cases are diagnosed and managed in peripheral hospitals, resulting in lower apparent percentages in tertiary-care datasets. Population based cohorts show that when the entire healthcare system is included, sarcoidosis can account for ±40% or more of all ILD diagnoses [13]. AIP: acute interstitial pneumonia; AFOP: acute fibrinous and organising pneumonia; AMP: alveolar macrophage pneumonia (formerly desquamative interstitial pneumonia (DIP)); COP: cryptogenic organising pneumonia; HP: hypersensitivity pneumonitis; iLIP: idiopathic lymphoid interstitial pneumonia; iNSIP: idiopathic nonspecific interstitial pneumonia; iPPFE: idiopathic cryptogenic organising pneumonia; LCH: Langerhans cell histocytosis; LAM: lymphangioleiomyomatosis; MCTD: mixed connective tissue disease; PAP: pulmonary alveolar proteinosis; RA: rheumatoid arthritis; RBILD: respiratory bronchiolitis interstitial lung disease; SLE: systemic lupus erythematosus; SSc: systemic sclerosis. This figure was created with BioRender.com.

Appreciating how immune dysregulation and epithelial vulnerability converge on this epithelial–immune–fibroblast axis is essential to understand, and ultimately treat, PF. It is currently unknown which cell type or interaction between cells initiates the fibrotic process, and which key events lead to progressive disease. A rich repertoire of preclinical models has been indispensable for dissecting PF. Figure 2 provides an overview of the main preclinical models available with the associated advantages and disadvantages.

FIGURE 2.

Overview of mouse models used to study pulmonary fibrosis (PF). Several mouse models are used to study PF, via different mechanisms [14–16, 19–22]. The mechanisms can be divided into damage-induced, trigger-induced and mimicking fibrosis processes. This overview shows the most widely used models, including the golden standard bleomycin, silica, transforming growth factor-β (TGF-β), asbestos and exposure to radiation. Their mode of action, advantages and disadvantages are presented. ILD: interstitial lung disease; ROS: reactive oxygen species. This figure was created with BioRender.com.

The bleomycin model, the most widely used, induces alveolar injury followed by neutrophil influx, monocyte recruitment, macrophage activation and ultimately fibrosis [14–16]. Fibrosis is preceded by (hyper)inflammation, resembling many PF patients, and blockade of innate pathways attenuates fibrosis, underscoring their upstream role [17, 18]. Yet bleomycin injury is self-limiting, so findings must be interpreted alongside chronic models. Silica and asbestos exposure induces persistent macrophage activation, inflammasome signalling and tertiary lymphoid structure (TLS) formation, mirroring occupational ILDs [19, 20]. In contrast, transforming growth factor-β (TGF-β) overexpression directly drives myofibroblast accumulation and dense collagen, useful for probing late-stage effector mechanisms [20]. Radiation and viral antigen models highlight how DNA damage and chronic antiviral responses perpetuate profibrotic immunity [21, 22]. Each model reflects only part of human disease, but together they reveal convergent immune circuits that drive fibroblast reprogramming.

Collectively, these models and human data position PF as a disease sustained by spatially organised immune–stromal circuits. Building on this foundation, the next sections examine how germline risk alleles prime these immune pathways, trace how epithelial injury cues recruit and programme innate and adaptive leukocytes to drive fibroblast activation, and translate these insights into measurable biomarkers and targeted therapeutic strategies.

Search strategy

We performed an extensive literature search using PubMed, Embase and Google Scholar to identify relevant studies related to innate and adaptive immunity in PF. Additional articles were found by screening cited literature until November 2025. We focused on genetics, with a specific interest for single-cell RNA sequencing (scRNA-seq) and spatial profiling over the past 5 years. Furthermore, we searched for literature related to immune cell subsets and recent clinical trials in context of PF as overarching disease, as well as specific conditions including hypersensitivity pneumonitis (HP) and connective tissue disease-ILD (CTD-ILD). Preference was given to recently published articles, but no specific time restriction was applied. Information related to clinical trials, in vitro studies and in vivo mouse experiments was mainly collected from original papers, but narrative and systematic reviews were also included in this review.

Genetic susceptibility and immune regulation in PF

Over the past decade, genome-wide studies have identified >50 variants influencing IPF and other fibrosing ILDs [23, 24]. Around 80% affect epithelial integrity or telomere biology, such as the MUC5B (mucin 5B) promoter variant and TERT/TERC (telomerase reverse transcriptase/telomerase RNA component) mutations [25, 26]. Crucially, about 20% involve immune regulation. Notable examples include Toll-interacting protein (TOLLIP) (e.g. rs5743890) single-nucleotide polymorphisms that alter Toll-like receptor (TLR) signalling in monocytes and macrophages [27], loss-of-function alleles in interleukin (IL)-1 receptor antagonist (IL1RN), which temper IL-1-driven inflammation in myeloid and dendritic cells (DCs) [28], missense variants in TLR3 that blunt viral RNA sensing and type-I interferon (IFN-I) production by epithelium and DCs [22], polymorphisms in complement receptor 1 that modify complement-mediated immune complex clearance by monocytes, B-cells and macrophages [29], and regulatory variants in TNFA that govern expression of tumour necrosis factor-α (TNF-α), a master cytokine in chronic inflammation and tissue remodelling [30]. Together, these variants suggest that epithelial fragility and immune hyper-reactivity cooperate to drive chronic inflammation and fibrosis, although the cell-specific consequences remain unclear.

Linking genotype to single-cell and spatial-omic profiling in well-phenotyped ILD cohorts will help clarify how these polymorphisms shape immune–stromal crosstalk [31]. Because such variants may hard-wire both epithelial fragility and immune dysregulation, the next section examines how injured AT2 cells signal danger to the immune system.

Epithelial injury and immune sensing

The alveolar epithelium, particularly the surfactant producing AT2 cell, is the frontline victim of noxious stimuli implicated in PF. Cigarette smoke, metal or silica dusts, viral infection, gastro-oesophageal micro-aspiration and radiation all induce endoplasmic reticulum stress, mitochondrial dysfunction and DNA damage in AT2 cells, culminating in apoptosis or senescence [16, 32] (figure 3). Genetically determined telomere shortening and misfolded surfactant proteins exaggerate this vulnerability, explaining why some individuals develop widespread epithelial attrition after seemingly modest insults [33]. Senescent AT2 cells adopt a pro-inflammatory “secretory” phenotype rich in IL-6, C-C motif chemokine ligand 2 (CCL2) and matrix metalloproteinase-7 (MMP-7), thereby priming the surrounding microenvironment for immune activation [34]. Dying or stressed epithelial cells release a spectrum of DAMPs, including extracellular ATP, high mobility group box-1 protein, S100-alarmins and oxidised mitochondrial DNA. These DAMPs engage pattern-recognition receptors such as P2X7, TLR4 and the cyclic-GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway on resident alveolar macrophages and DCs [35, 36]. Concomitantly, epithelial IL-33, a canonical alarmin stored in the nucleus, escapes into the extracellular milieu where it activates suppression of tumorigenicity 2 (ST2)-bearing type 2 innate lymphoid cells (ILC2s) and T-helper 2 (Th2) lymphocytes to produce IL-13 [37]. Collectively, these signals convert a local epithelial injury into a broad immune alert. Intracellular stress also provokes assembly of the NOD-like-receptor-family protein 3 (NLRP3) inflammasome in both epithelial cells and macrophages, resulting in caspase 1-dependent maturation of IL-1β and IL-18 [38]. IL-1β amplifies neutrophil-recruiting chemokines (C-X-C motif chemokine ligand (CXCL) 1 and CXCL8) and upregulates vascular adhesion molecules, whereas IL-18 fosters IFN-γ production by natural killer (NK) and Th1 cells [39]. Meanwhile, TLR3 engagement by viral double-stranded RNA enhances IFN-I release and modulates DC maturation, a pathway rendered hypomorphic by the IPF-associated TLR3 L412F variant [22]. Experimental depletion of AT2 cells in transgenic mice is sufficient to recruit C-C chemokine receptor 2 (CCR2)⁺ monocytes and trigger a fibroproliferative response that mirrors human disease, underscoring the primacy of epithelial cues in launching the fibrotic programme [40]. Recent single-cell and spatial transcriptomic studies also demonstrate marked attenuation and transcriptional reprogramming of alveolar type-1 (AT1) cells in IPF, including loss of mature AT1 markers, impaired gas exchange differentiation states, and emergence of transitional KRT8⁺/CLDN4⁺ (keratin 8/claudin 4) epithelial cells occupying the injured alveolar surface [8, 41, 42]. Conversely, pharmacological inhibition of STING or NLRP3 attenuates early inflammatory signalling and blunts downstream collagen deposition in bleomycin-exposed lungs [43–45].

FIGURE 3.

Development of pulmonary fibrosis (PF). Important mechanisms and factors associated with PF are shown, as described in this review. Primary injury of the alveolar type (AT) 2 cells leads to a pro-inflammatory environment, characterised by interleukin (IL)-6 and tumour necrosis factor-α (TNF-α). This pro-inflammatory environment can switch to profibrotic in the presence of IL-13, transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF). TGF-β drives the activation of fibroblasts and subsequent differentiation into α-smooth muscle actin⁺ (α-SMA⁺) myofibroblasts. DAMP: damage-associated molecular patterns; ECM: extracellular matrix; ILC2: type 2 innate lymphoid cell; NK: natural killer; TLS: tertiary lymphoid structure. This figure was created with BioRender.com.

Thus, epithelial injury is far more than a passive lesion; it actively orchestrates an innate danger response that mobilises and reprogrammes immune cells. In the next section we dissect how these recruited and resident immune populations perpetuate chronic inflammation and, through their cytokine repertoire, tip the balance from tissue repair to unabated fibrogenesis.

Innate immune cells play a central role in the epithelial–immune–mesenchymal cascade

Immune cells recruited to the injured alveolar niche perpetuate chronic inflammation and fibroblast activation. Table 1 summarises the major innate and adaptive immune cell subsets implicated in IPF and related fibrotic ILDs.

TABLE 1.

Overview of innate and adaptive immune cell subsets implicated in idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF), with selected mechanistic roles and clinical associations

Cell type	Role in IPF	Role in PPF	References
Neutrophils	Recruited via IL-8 Release neutrophil elastase and NETS that activate fibroblasts Increased BALF counts predict mortality	Increased BALF neutrophils and NETs associated with progression in HP and CTD-ILD	[10, 11, 79, 81–86, 183, 187–192]
Macrophages	SPP1+ and CCL18+ subsets drive fibroblast activation High serum CCL18 predicts poor survival	Elevated SPP1/osteopontin and CCL18 levels in CTD-ILD and HP associated with progression	[9, 54–56, 59, 184–186, 199–201]
Monocytes	Expanded numbers with heightened type-I interferon responses CCR2+ recruitment yields pathogenic macrophages	Monocytosis and elevated CCL2 linked to progression in RA-ILD and CTD-ILD	[13, 64, 66, 67, 188, 202–205]
ILCs	Increased ILC2 in IPF lungs Elevated IL-13 and IL-17A levels	Increased IL-13 and IL-17A in SSc-ILD and RA-ILD ILC1-associated IL-15 correlates with impaired lung function	[13, 100, 102]
Mast cells	Numbers correlate with fibrosis severity Histamine and TGF-β1 release promote fibrogenesis	Increased mast cells in HP associated with more severe fibrosis	[87–89]
NK cells	Reduced number and function Impaired clearance of senescent cells amplifies fibrosis	NK dysfunction permits senescent cell accumulation and disease progression	[90, 91, 96, 97]
DCs	Decreased circulating cDC2; immature DCs accumulate in fibrotic foci Elevated Flt3L may reflect protective response	Functional heterogeneity suggested; some subsets may have antifibrotic effects	[104, 107–110]
CD4+ T-cells	Shift from Th1/Treg (protective) toward Th2/Th17/Tfh (profibrotic) High CXCL13 predicts worse outcomes	Similar Th2/Th17 predominance and Treg dysfunction reported in CTD-ILD and HP	[17, 115, 117, 121–127, 130–136, 141]
CD8+ T-cells	Numbers correlate with dyspnoea and reduced FVC Tc1 (IFN-γ) protective, Tc2 (IL-4/IL-13) profibrotic	Likely similar profibrotic skewing in CTD-ILD	[103, 115, 142–145]
B-cells	TLS-associated memory B-cells and plasmablasts drive autoimmunity BAFF elevated Autoreactive antibodies linked to poor prognosis	Reduced regulatory B-cells Increased BAFF and autoantibodies (ATA, ACPA) in SSc-ILD and RA-ILD Elevated IgA in BALF predicts poor survival in HP	[129, 141, 150–152, 154–156, 159–169]

ACPA: anti-citrullinated protein antibody; ATA: anti-topoisomerase antibody; BAFF: B-cell activating factor; BALF: bronchoalveolar lavage fluid; CCL: chemokine ligand; CCR2: C-C chemokine receptor 2; CD: cluster of differentiation; cDC2: conventional type 2 dendritic cell; CTD-ILD: connective tissue disease–interstitial lung disease; CXCL13: C-X-C motif chemokine ligand 13; DC: dendritic cell; Flt3L: FMS-like tyrosine kinase 3 ligand; FVC: forced vital capacity; HP: hypersensitivity pneumonitis; IFN-γ: interferon-gamma; IgA: immunoglobulin A; IL: interleukin; ILC: innate lymphoid cell; NET: neutrophil extracellular trap; NK: natural killer; nRTK: nonreceptor tyrosine kinase; PDE4: phosphodiesterase 4; RA-ILD: rheumatoid arthritis–interstitial lung disease; SMAD3: mothers against decapentaplegic homologue 3; SPP1: secreted phosphoprotein 1; SSc-ILD: systemic sclerosis–interstitial lung disease; Tc: cytotoxic T-cell; Tfh: follicular helper T-cell; TGF-β1: transforming growth factor beta 1; Th1: T-helper 1 cell; Th2: T-helper 2 cell; TLS: tertiary lymphoid structure; Treg: regulatory T-cell.

Temporal contribution of monocytes and macrophage subsets to fibrosis pathogenesis

Epithelial danger signals recruit diverse innate immune cells, with macrophages central to fibrosis. Human lungs contain alveolar, interstitial and monocyte-derived macrophages [46]. Importantly, these subsets show mixed phenotypes beyond the classical M1/M2 paradigm and their activation is tightly regulated in the lung's tissue context to avoid excessive inflammation [47]. Alveolar macrophages are rapidly licensed by IFN-γ and DAMPs to adopt a pro-inflammatory state characterised by robust production of TNF-α [48], IL-1β via inflammasome activation [49] and reactive oxygen species that amplify local tissue injury [50]. As the inflammatory milieu becomes dominated by IL-4 and IL-13, the predominant macrophage phenotype shifts to profibrotic, characterised by expression of arginase-1, chitinase-like proteins and secretion of profibrotic mediators such as TGF-β and CCL18 [51, 52]. CCL18 acts as a chemoattractant for profibrotic Th2 cells, but also directly induces a profibrotic phenotype in fibroblasts, inducing fibroblast growth factor 2 excretion and collagen-1 and α-smooth muscle actin (α-SMA) expression through CCR6 [53]. High circulating CCL18 levels (>150 ng·mL⁻¹) independently predict mortality in IPF and systemic sclerosis-ILD (SSc-ILD), underscoring its pathogenic relevance [9, 54, 55].

Single-cell transcriptome analysis of IPF and healthy lung tissue revealed distinct macrophage subsets that are not limited to a single anatomic compartment in healthy lungs [56, 57]. The first comprehensive single-cell atlas of IPF lungs by Adams et al. [41] extended these observations by identifying aberrant basaloid epithelial cells lining the edges of fibroblast foci together with a profibrotic macrophage archetype occupying the same niche. This spatial co-localisation of disease-specific epithelial and myeloid populations further supports the concept of organised innate immune–epithelial crosstalk within the fibrotic niche. FABP4 and INHBA expressing alveolar macrophages are most abundant in the upper lobes of IPF lungs, representing an earlier, more inflammatory disease stage, and decrease gradually towards the lower lobes, representing late-stage fibrotic disease [56]. Conversely, a distinct subset of macrophages expressing SPP1 and MERTK was markedly increased in the lower lobes of IPF lungs, and increased compared to healthy lung tissue [56]. This is confirmed by spatial transcriptomic analysis of IPF lung tissue, in which the proportion of SPP1-expressing macrophages was increased and higher SPP1 expression was associated with higher pathology scores [58]. SPP1 encodes osteopontin, an ECM protein that has strong profibrotic effects on fibroblasts and epithelial cells, inducing proliferation and migration, and production of collagen type I and profibrotic MMPs [59, 60]. Macrophage-expressed galectin-3 binds to CD98 on fibroblasts to enhance TGF-β receptor signalling, whereas fibroblast galectin-9 feeds back to polarise macrophages toward an M2 phenotype, creating a self-reinforcing profibrotic loop [61].

The third population of FCN1 and CD14 expressing macrophages remained stable between IPF and healthy lungs [56]. ScRNA-seq analysis in IPF and fibrotic HP revealed that both FCN1/CD14- and SPP1/MERTK-expressing macrophages can be derived from circulating monocytes, whereby CD14 expressing cells may reflect “early” and SPP1/MERTK-expressing cells may reflect “late” monocyte-derived profibrotic macrophages [62]. Circulating classical (CD14⁺CD16⁺) and intermediate (CD14⁺CD16⁺) monocytes are expanded in progressive PF compared to stable PF, and classical monocyte blood count is an independent predictor of transplant-free survival [63–65]. In vitro, monocytes from IPF patients show an enhanced inflammatory phenotype with an increased response to IFN-I stimulation compared to healthy controls [66]. Chemokine CCL2 produced by stressed epithelium and fibroblasts guides CCR2⁺ classical monocytes into the alveolar wall, where they differentiate into collagen-expressing, tissue-remodelling macrophages [65, 67]. CCR2⁺ macrophages accumulate in fibrotic lung tissue and studies in mice show that monocyte-derived macrophages may be the main pathogenic subset, with a limited role for tissue-resident subsets [68–70]. Importantly, macrophages show a high level of plasticity. For example, monocyte-derived macrophages were shown to adopt an alveolar phenotype, replacing resident alveolar macrophages during and after fibrosis [71, 72]. Although the relative contribution of different macrophage subsets to PF remains to be elucidated, it is clear that they are major drivers of both the inflammatory and fibrotic phase of the disease. Beyond transcriptional and phenotypic heterogeneity, macrophages and other immune cells in fibrotic lungs are increasingly recognised to undergo profound metabolic reprogramming. In experimental models of lung fibrosis, alveolar macrophages from bleomycin- and TGF-β1-induced fibrotic lungs adopt a profibrotic phenotype that is strictly dependent on enhanced glycolysis, whereas pharmacologic inhibition of key glycolytic enzymes reverses this programme and attenuates collagen deposition [73]. In chronic lung disease, airway macrophages flexibly switch between oxidative phosphorylation, fatty acid oxidation and aerobic glycolysis in response to environmental cues, using glycolysis to sustain rapid cytokine production and mitochondrial metabolism to support tissue-remodelling functions [74]. From a broader immunometabolic perspective, fibrotic tissues are characterised by niches in which metabolic pathways in macrophages, T-cells and B-cells, including glycolysis, glutaminolysis and fatty-acid metabolism, are rewired to favour pro-inflammatory, profibrotic phenotypes over regulatory or reparative states [75, 76]. These data collectively suggest that targeting metabolic checkpoints in immune cells may complement existing antifibrotic therapies and offer new strategies to modulate the inflammatory microenvironment in PF.

Neutrophils and mast cells interact with fibroblasts to support fibrogenesis

Neutrophils, though traditionally viewed as bystanders, are abundant in fibrotic lungs, and higher counts in BALF or blood independently predict mortality in IPF and HP [10, 77–79]. IL-8, produced by alveolar macrophages and epithelial cells, drives neutrophil migration into the lungs [11, 80]. Once present, neutrophils promote fibrogenesis by releasing neutrophil elastase, which stimulates fibroblast proliferation and myofibroblast differentiation through TGF-β activation [81, 82]. Furthermore, neutrophils excrete neutrophil extracellular traps (NETs), which induce transdifferentiation and activation of lung fibroblasts, inducing α-SMA and collagen production, whereby the latter is partly dependent on IL-17 present in the NETs [83]. Furthermore, NETs directly induce epithelial and endothelial cell death through histone-induced cytotoxicity [84]. Interestingly, depleting neutrophils during the inflammatory phase of bleomycin injury does not alter fibrosis, suggesting their role is largely fibrotic rather than inflammatory [85]. However, targeting neutrophils may be risky, as impaired host defence and increased bacterial burden accelerate IPF progression [86].

Mast cells, though less studied, increase with fibrosis severity. In vitro, they induce fibroblast activation and myofibroblast differentiation [87–89]. Mechanical stress triggers mast cell degranulation and histamine release, which activates TGF-β1 signalling [88]. BALF histamine levels are increased in IPF patients and mast cell deficient mice are protected against bleomycin-induced PF, suggesting they support fibrogenesis [89].

NK cell dysfunction supports accelerated cellular senescence

Cellular senescence is characterised by irreversible cell-cycle arrest and the production of pro-inflammatory cytokines, called the senescence-associated secretory phenotype [90]. Ageing-associated cellular stressors, also implicated in IPF, including telomere attrition, oxidative stress and DNA damage, induce this cellular state [90]. Cellular senescence of AT2 cells and fibroblasts is increased particularly in IPF, but also in other ILD types [90, 91]. Importantly, the secretory phenotype of these senescent cells includes many profibrotic cytokines, including TGF-β [92–94]. NK cells are essential for the removal of senescent cells, which they recognise through expression of NKG2D receptors that bind to senescent cell ligands [95]. Compromised NK cell numbers and function are observed in IPF patients, particularly in the lower lobes, correlating with severe pathology [96]. In vitro experiments showed that a profibrotic microenvironment reduced NK cell recruitment and cytotoxic capacity, and induced NK cell senescence [97]. Furthermore, NK cell depletion in bleomycin-exposed mice enhanced senescent cell accumulation and collagen deposition in the lungs [97]. Together, senescent epithelial and mesenchymal cells, compounded by impaired NK cell surveillance, create a self-perpetuating cascade that sustains inflammation and drives fibrogenesis.

ILC2s induce fibrosis through activation of macrophages and fibroblasts

Epithelial alarmins IL-33 and thymic stromal lymphopoietin (TSLP) strongly activate ILC2s [98]. IL-33 is essential for bleomycin-induced fibrosis, driving IL-13 and TGF-β production by macrophages and IL-13 release from ILC2s [99]. Both IL-33/TSLP levels and ILC2 numbers are elevated in IPF lungs, where ILC2s colocalise with fibroblast foci [100–102]. Furthermore, ILC2s from IPF patients showed decreased expression of IFNGR1, which encodes the receptor for IFN-γ, an important inhibitor of ILC2 activity and cytokine production [101]. IL-13 production by ILC2s stimulates TGF-β production by macrophages, and induces collagen deposition by lung fibroblasts [102, 103].

Dual role for DCs in PF

DCs accumulate in fibrotic foci, presenting antigens from injured epithelium to lymphocytes in bronchiole-associated lymphoid tissue or TLS [104]. In experimental PF, DC influx correlates with memory T-cell expansion and blocking DC maturation reduces collagen deposition [105]. In IPF patients, DC numbers in the circulation are significantly reduced [106], while immature DCs accumulate in lungs via chemokines such as CCL19, CCL20, CCL22 and CXCL12 [104, 107, 108]. However, recent studies suggest functional heterogeneity. CD103⁺ DCs interact with fibroblasts to promote fibrogenesis via noncanonical aryl hydrocarbon receptor signalling and IL-6 production, enhancing IL-17 lymphocytes and collagen deposition [109]. In contrast, DCs were shown to have a protective role in a TGF-β1 adenovirus transfer-induced mouse model [110]. This protective function is dependent on FMS-like tyrosine kinase 3 ligand, a DC-specific growth factor, which was found to be increased in serum and lung tissue of IPF patients [110]. Differences between the mouse models used may underlie these discrepancies, with the bleomycin model showing extensive inflammation, where this is not a feature of the TGF-β1 adenovirus-induced model.

Together, these innate immune pathways establish a profibrotic milieu that sets the stage for adaptive immune responses.

Adaptive immunity further entrenches chronic inflammation

Adaptive immunity sustains and progressively entrenches the inflammatory microenvironment that seeds irreversible scar formation. One histopathological hallmark of this process is the emergence of ectopic TLSs; lymphoid aggregates that develop under conditions of chronic inflammation in nonlymphoid organs, including lungs [111]. There, TLSs maintain and activate local and systemic T- and B-cell responses. Increased numbers of TLSs in the lungs are observed in patients with advanced IPF and HP is defined by the presence of TLSs, suggesting involvement of B- and T-lymphocytes in both diseases [111–113]. Spatial transcriptomic analysis of IPF and healthy lung tissue revealed an immune niche in IPF that is not present in healthy lungs [114]. In these immune foci, B- and T-cells cluster together with ectopic PLVAP⁺ (plasmalemma vesicle-associated protein) endothelial cells, which may have the capacity to recruit adaptive immune cells through the CXCR4–CXCL12 axis.

CD4⁺ T-cell polarisation

CD4⁺ T-lymphocytes heavily influence whether lung inflammation resolves or progresses to the scarred architecture of PF. After the antigen is presented on major histocompatibility complex class II, naïve CD4⁺ T-cells polarise into Th1, Th2, Th17, Th9, follicular-helper (Tfh) and some regulatory (Treg) subsets, each guided by a signature cytokine-transcription factor programme [115]. In health, an early type 1 milieu limits fibroblast activation, whereas sustained injury tips the balance toward type 2 immunity, thereby entrenching ECM deposition.

During the initial inflammatory phase, Th1 cells dominate. Their key product, IFN-γ, represses TGF-β-driven fibroblast activation, inhibits type 2 macrophage polarisation and restricts Th2 expansion [115, 116]. Concordantly, both IFN-γ and its chemotactic axis CXCL10–CXCR3 are depleted in BALF from IPF patients [115, 117], and mice lacking CXCL10 develop exaggerated collagen deposition, whereas CXCL10 overexpression is protective [118]. Despite these observations, recombinant IFN-γ was ineffective in clinical IPF trials [119], implying that therapeutic benefit depends on timing or co-intervention.

As epithelial damage persists, immunity skews toward Th2 immunity. IL-4, IL-5 and IL-13, together with TGF-β, drive myofibroblast differentiation and ECM accumulation; dendritic- and epithelial-derived chemokines CCL17 and CCL22 amplify this loop and are elevated in bleomycin-injured mice [120] and in BALF or serum from IPF and HP patients [121–125]. Th2-derived IL-4/IL-13 activates signal transducer and activator of transcription 6 (STAT6) in fibroblasts, amplifying TGF-β production and further recruiting CCR4⁺ Th2 cells [120]. In parallel, Th17 cells expand under the combined influence of TGF-β and IL-6, a cytokine milieu distinct from Th2 polarisation. Importantly, these programmes are not mutually exclusive but often co-exist within fibrotic lungs. Th17-derived IL-17A reinforces fibrosis by enhancing TGF-β signalling in fibroblasts and inducing IL-6 production by fibroblasts and other resident cells [17, 126, 127]. A loss of counter-regulatory Tregs exacerbates this trajectory, whereas restoring the Th17/Treg balance blunts bleomycin-induced fibrosis [115, 128]. Additional subsets further refine the adaptive response. Th9-derived IL-9 can stimulate fibroblasts and mast cells, and blocking IL-9 limits silica-induced fibrosis, although opposite effects occur in bleomycin models, likely reflecting differences in injury mechanism and the timing of Th9/Treg interactions. CXCL13-driven recruitment of CXCR5⁺ Tfh cells fosters TLSs, sustaining local B-cell activation; higher CXCL13 independently predicts faster decline and poorer survival in IPF [129–131].

Thus, an early Th1/Treg-skewed response acts as an antifibrotic brake, whereas chronic Th2/Th17 activity, augmented by Th9 and Tfh circuits, locks the lung into a self-perpetuating profibrotic state.

Treg heterogeneity

Tregs influence PF in a stage-dependent, bidirectional manner. In earlier studies in IPF, reduced Treg numbers in BALF and blood correlated with greater radiographic and physiological severity, and animal work showed that an imbalance between activated versus resting Tregs, or a low Treg/Th17 ratio, favours collagen deposition [132–135]. A temporal model reconciles these findings: during the acute injury phase, Treg-derived TGF-β contributes to wound healing fibroblast activation and can also promote further Treg induction. Once injury stabilises, however, expanding Tregs primarily exert suppressive functions, curbing Th17 activity and limiting additional fibroblast recruitment, thereby restraining further scarring [136]. IL-9 released by Th9 cells can tilt this Treg–Th17 balance toward fibrosis, as neutralising IL-9 reduces collagen deposition in multiple bleomycin and silica models [137–140]. However, recent scRNA-seq data has shed new light on these findings. In a study comparing stable with progressive IPF, Treg numbers in the circulation were increased in the progressive group. Levels of CCL22 and CCL18, which are ligands for CCR4 and CCR8 expressed by Tregs, respectively, were increased in lung homogenates, suggesting increased migration of Tregs into the lungs in progressive IPF [65]. This was confirmed in two other scRNA-seq studies of lung tissue, where Treg numbers were increased in IPF versus control samples [62]. Importantly, high blood Treg numbers were associated with a shorter transplant-free survival in IPF [41]. Further analysis of Treg phenotype and function in lungs of progressive IPF patients may reveal whether these cells adopt a profibrotic phenotype or fail to inhibit other profibrotic cells.

A further layer of adaptive dysregulation involves CXCL13. This chemokine, pivotal for TLS formation, recruits CXCR5⁺ Tfh cells [129]. Elevated CXCL13 in IPF lung tissue and plasma predicts faster functional decline and poorer survival, and expanded Tfh populations accumulate within fibrotic foci [130, 131, 141]. CXCL13-driven TLSs therefore sustain local, self-reactive B- and T-cell responses that reinforce ongoing fibrogenesis. Together, these data position Tregs, IL-9/Th9 signalling and the CXCL13–Tfh axis as stage-specific adaptive checkpoints in PF.

CD8⁺ T-cell exhaustion versus cytotoxicity

CD8⁺ T-cells, though traditionally recognised for their cytotoxic clearance of infected or malignant targets [115], are increasingly implicated in PF. In IPF, higher CD8⁺ T-cell counts correlate with worse dyspnoea and lower FVC [142]. Like their CD4 counterparts, naïve CD8⁺ T-cells diversify into cytotoxic T-cell type 1 (Tc1), Tc2, Tc9, Tc17, Tc22 and regulatory phenotypes [143]. Tc1-derived IFN-γ predominates during early inflammation and is generally antifibrotic, whereas Tc2-derived IL-4/IL-13 can engage the profibrotic TGF-β/STAT6 axis [103, 115, 143–145].

scRNA-seq of IPF lungs revealed several CD8⁺ T-cell trajectories, including cytotoxic, metabolically reprogrammed and exhaustion-skewed states [146]. Profibrotic signalling pathways, including ECM organisation and TGF-β responses, were enriched in several of these subpopulations and predicted ligand–receptor maps showed extensive crosstalk with fibroblasts and macrophages. These data suggest that distinct CD8⁺ T-cell subsets may both drive and modulate fibrogenesis, rather than serving as passive bystanders.

These quantitative and qualitative changes in T-cell subsets occur within a broader state of “immunoparalysis”, characterised by sustained antigen exposure and upregulation of the – programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis. In explanted IPF lungs and mediastinal lymph nodes, PD-1⁺ T-cells accumulate within fibrotic regions and tertiary lymphoid structures, where they display features of functional exhaustion but retain the capacity to produce profibrotic cytokines such as IL-17A. In parallel, PD-1 signalling on myeloid cells has been implicated in restraining antimicrobial responses while maintaining chronic inflammation. Human and experimental data from Karampitsakos et al. [147] and Celada et al. [148] therefore support PD-1-driven immunoparalysis as a hallmark of adaptive immune dysregulation in PF and a potential, but double-edged, therapeutic target.

B-cell and plasma cell dysregulation

In IPF lungs, TLSs contain class switched memory B-cells and plasmablasts; a higher TLS score correlates with faster FVC decline [149]. Once activated via antigen plus T-cell help, B-cells differentiate into antibody-secreting cells and release cytokines that are either pro-inflammatory or immunoregulatory. IL-10-producing B-cells restrain T-cell and Tfh-cell activity, yet their numbers are reduced in IPF and SSc-ILD [129, 150–152], tilting the balance toward unchecked immunity. Survival of autoreactive clones is further enhanced by B-cell activating factor (BAFF); circulating and pulmonary BAFF levels rise across IPF and CTD-ILD and track with disease progression and mortality [153–156]. Whether BAFF primarily drives autoimmunity or directly fuels fibrosis remains unresolved, but a single-case report suggests that BAFF blockade with belimumab can stabilise CTD-ILD when added to immunosuppression [157, 158].

Beyond these changes in B-cell homeostasis, recent mechanistic studies highlight intrinsic abnormalities in B-cell receptor (BCR) signalling. In IPF, B-cells show aberrant activation of the BCR pathway, including enhanced Bruton's tyrosine kinase (BTK) signalling, suggesting that altered antigen responsiveness may contribute to fibrogenesis [141]. Treatment with the antifibrotic nintedanib modulates BCR signalling in B-cells from IPF patients, pointing to immunomodulatory effects beyond its mesenchymal targets [156]. Together, these findings highlight BCR signalling as a therapeutic checkpoint, potentially targetable with BTK inhibitors.

B-cells actively contribute to fibrosis through antigen presentation and T-cell co-stimulation, by producing autoantibodies against self-antigens such as annexin-A1, periplakin, vimentin and topoisomerase, and by releasing cytokines that deregulate T-cell and Tfh activity via loss of IL-10⁺ B-cells [128, 141, 149–156, 159–169]. In addition, elevated BAFF levels promote the survival of autoreactive clones [152–155] and CXCL13-driven TLS formation sustains local B- and T-cell responses that reinforce fibrogenesis [128–130, 141].

Collectively, these adaptive mechanisms converge with innate immune pathways to create a persistent profibrotic milieu (summarised in figure 3 and table 1), setting the stage for fibroblast activation and immune-mediated tissue remodelling.

Fibroblast activation and immune-mediated tissue remodelling

Chronic immune activation reprogrammes mesenchymal cells. TGF-β, IL-13, IL-6, platelet-derived growth factor and connective-tissue growth factor (CTGF) drive fibroblast proliferation, metabolic rewiring and differentiation into α-SMA⁺ myofibroblasts [6, 103, 170]. Myofibroblasts deposit collagen I/III, fibronectin and periostin while downregulating matrix-degrading enzymes and upregulating inhibitors, shifting the ECM balance toward net deposition [171].

Mechanical feedback sustains this state. Integrin αvβ6 on wounded epithelium activates latent TGF-β and matrix stiffening augments integrin-mediated signalling. Several αvβ6 integrin antagonists have entered clinical testing in IPF and PPF, but so far they have not delivered the expected FVC benefit, and the αvβ6/αvβ1 inhibitor bexotegrast (PLN-74809) failed to demonstrate a favourable risk–benefit profile in the BEACON-IPF phase 2b/3 trial, leading to discontinuation of IPF development [172]. These mixed results illustrate that simply maximally suppressing TGF-β activation may overshoot physiological needs: persistent TGF-β overexpression is a central driver of fibroblast activation and ECM deposition, yet basal TGF-β signalling is indispensable for maintaining immune tolerance and tissue homeostasis. Excessive or nonselective TGF-β blockade could therefore impair antimicrobial defence and promote acute exacerbations, emphasising that future strategies should aim to restore TGF-β activity to homeostatic levels rather than complete pathway inhibition. Fibroblast populations are heterogeneous; scRNA-seq identified at least three major subsets in PF lungs, namely canonical COL1A1⁺ (collagen type I alpha 1 chain) proliferative fibroblasts, HAS1⁺/CXCL14⁺ inflammatory fibroblasts that secrete CCL2 and IL-6, and ACTA2⁺ myofibroblasts enriched in fibrotic foci [8]. Lineage tracing studies suggest that inflammatory fibroblasts, corresponding to the HAS1⁺/CXCL14⁺ (hyaluronan synthase 1/C-X-C motif chemokine ligand 14) subset, act as intermediates that convert into myofibroblasts under sustained IL-1β and TGF-β exposure, thereby providing a mechanistic link between chronic inflammation and scar formation [41, 173, 174]. Across multiple single-cell atlases, a population of CTHRC1⁺ (collagen triple helix repeat containing 1) fibroblasts/myofibroblasts has emerged as a dominant effector subset located within fibroblastic foci. CTHRC1⁺ cells produce high levels of collagens and other extracellular matrix components, display enhanced migratory capacity, and interact closely with profibrotic macrophages via ligand–receptor pairs enriched for TGF-β and osteopontin signalling. These features position CTHRC1⁺ fibroblasts as a key stromal hub that links chronic immune activation to irreversible tissue remodelling [173, 175]. Thus, cytokine-primed, mechanically reinforced myofibroblasts execute tissue remodelling, but their activation is inseparable from the immune context that nurtures them.

The following section synthesises insights from experimental models and human biospecimens to illustrate how these epithelial–immune–mesenchymal interactions materialise in vivo and how they can be quantitatively monitored in patients.

The immune system as a therapeutic target in PF

For much of the past decade, exploring possibilities for broad immunomodulation in IPF waned after the PANTHER-IPF trial showed excess mortality and hospitalisation with prednisone, azathioprine and N-acetyl-cysteine versus placebo [176]. Post hoc analyses suggested harm clustered in TOLLIP risk-allele carriers and patients with short telomeres, reframing the question to which immune pathways to target, in whom and when [177].

In recent years, many clinical trials have sought more effective treatments for IPF and PPF. Most did not achieve a significant effect in the primary end-point of FVC decline and several study compounds also had adverse effects [176, 178]. Recent phase II and III trials with immune-modulating drug candidates are shown in figure 4, distinguishing between IPF and IPF/PPF patient inclusion. Notably, many studies involve TGF-β, a key contributor to fibrosis [179].

FIGURE 4.

Emerging drug targets for idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). Overview of mechanisms and compounds that have been tested in IPF and PPF. Besides approved drugs pirfenidone and nintedanib, relevant clinical trials are also included. A distinction is made between inclusion of IPF patients only (light blue), or both IPF and PPF patients (dark blue). Green indicates positive effects in phase III trials, orange marks trials that are currently under investigation in a phase II or phase III trial and red represents clinical trials that did not meet the primary end-points. CSF1R: colony stimulating factor 1 receptor; CTGF: connective tissue growth factor; FGFR: fibroblast growth factor receptor; LPA: lysophosphatidic acid; nRTK: nonreceptor tyrosine kinase; p38 MAPK: p38 mitogen-activated protein kinase; PCBP3: poly(Rc) binding protein 3; PDE4: phosphodiesterase 4; PDGFR: platelet-derived growth factor receptor; PFKFB3: 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; PTX: pentraxin; SMAD3: mothers against decapentaplegic homologue 3; TGF-β: transforming growth factor-β; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor. This figure was created with BioRender.com.

Mouse models are vital for studying disease mechanisms and evaluating therapies [180], but preclinical study outcomes often did not translate well to clinical trials. Several agents that showed robust efficacy in murine fibrosis models failed to meet phase III end-points in IPF, including the anti-CTGF antibody pamrevlumab [181] and the pentraxin-2 biologic PRM-151/zinpentraxin alfa [182]. These setbacks underscore the limitations of acute injury models, as well as differences in disease stage, pharmacokinetics, and endpoint selection between mice and patients. Better chronic/remodelling models, biomarker-guided enrolment and end-points aligned to human disease trajectories will likely improve translatability.

Together, these trial outcomes and translational gaps highlight the need to refine experimental models and patient selection strategies, setting the stage for pathway-directed and endotype-matched approaches that target the immune mechanisms sustaining fibrosis. Within this framework, several innate circuits have emerged, including monocyte recruitment via CCL2–CCR2 [67–70, 183–186], profibrotic macrophage programmes (CCL18 [9, 52–55] and SPP1⁺ (secreted phosphoprotein 1) macrophages [56, 59, 60, 187–192]), neutrophil elastase and NETs that couple injury to fibroblast activation [81–86, 177, 179, 193–198], epithelial alarmins such as IL-33 and TSLP [98–102, 199–205], mast cell-mediated TGF-β activation [87–89], and context-dependent DC subsets [104–110, 206–208].

On the adaptive side, therapeutic attempts to block IL-13 have failed clinically despite convincing preclinical signals [103, 115, 206]. TLS-linked Tfh programmes, particularly through the CXCL13–CXCR5 axis, correlate with faster decline and poorer outcomes [125–127, 137, 143]. In parallel, B-cell-related pathways including elevated BAFF [149–152] and aberrant B-cell receptor signalling [152] support biomarker-guided targeting of the BAFF/BTK axis.

At the stromal interface, αvβ6 integrin and galectin-3 act as key checkpoints that activate latent TGF-β and reinforce fibroblast–immune crosstalk [155, 157, 158]. Other pathways currently under investigation include the LPA (lysophosphatidic acid)–LPA₁ axis [209], CTGF signalling [181], macrophage-directed modulation [182] and metabolic rewiring of fibroblasts and immune cells through PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3) [210].

Two antifibrotic agents, pirfenidone and nintedanib, are now standard of care for IPF and other forms of progressive fibrosis. Although developed for their direct antimesenchymal effects, both drugs exhibit measurable immune activity. Pirfenidone downregulates IL-1β and TNF-α transcription in macrophages and attenuates NLRP3 inflammasome activation, thereby reducing IL-1β-dependent fibroblast priming [211]. Nintedanib modulates B-cell receptor signalling in IPF and has a target profile that includes SRC-family kinases, though direct inhibition in B-cells has not been demonstrated [156], and blocks KIT signalling in mast cells, limiting histamine release and TGF-β activation [87]. Nintedanib has also been shown to dampen T-cell activation and cytokine production and to prevent or even reverse M2-like macrophage polarisation in vitro [212], highlighting broader immunomodulatory actions on both adaptive and innate compartments beyond its direct antiproliferative effects on fibroblasts. These pleiotropic effects likely complement their antiproliferative actions on fibroblasts and may partially explain their efficacy across heterogeneous ILD phenotypes.

Nerandomilast is a next generation, highly selective phosphodiesterase-4B inhibitor that has completed two pivotal phase III studies. In FIBRONEER-IPF [193] and FIBRONEER-ILD [194], the agent significantly slowed the annual decline in FVC, with the ILD cohort also showing a nominal reduction in all-cause mortality. Preclinical work demonstrated that selective phosphodiesterase 4 (PDE4) B blockade elevates cAMP in monocytes, macrophages and T-cells, suppressing TNF-α, IL-6 and IL-17 while sparing PDE4D toxicity [195]. Nerandomilast also dampens neutrophil recruitment and type 2 macrophage activation, reducing collagen in bleomycin models [196, 197]. These data support nerandomilast as both immunomodulatory and antifibrotic, exemplifying how pathway-directed intervention can complement existing therapy.

Conclusion and future perspectives

Advances in genetics, high-resolution tissue profiling and translational modelling have converged on a unifying view: PF is not merely the outcome of epithelial fragility or fibroblast autonomy, but the emergent product of a tridirectional dialogue between injured epithelium, an immune system shaped by genetic and epigenetic predisposition, and a mechanically responsive mesenchyme. Innate and adaptive immune cells function both as initiators, by sensing epithelial danger cues and releasing profibrotic cytokines, and as amplifiers, by sustaining myofibroblast activation through soluble mediators, cell–cell interactions, and matrix remodelling [6, 8]. The common trajectory across current approaches is a shift from indiscriminate suppression toward precision strategies that target discrete immune circuits, guided by biomarkers able to identify the dominant drivers in each patient.

Importantly, fibrotic ILDs exist along a clinical spectrum of immune involvement. CTD-associated ILDs represent strongly immune-driven conditions in which immunomodulatory therapies are already established for both pulmonary and extrapulmonary manifestations. At the opposite end, IPF is fibrosis-dominant, where broad immunosuppression has proven harmful and antifibrotics are the cornerstone of therapy. In between lies fibrotic HP and related disorders, where inflammation and fibrosis co-exist to variable degrees. Positioning novel immune-directed interventions within this spectrum is essential, as therapeutic opportunities and risk–benefit profiles may differ fundamentally between immune-dominant and fibrosis-dominant disease entities.

Antifibrotics such as pirfenidone and nintedanib extend survival but mainly slow progression and under-address immune drivers, which may dominate in early disease [198]. Mixed outcomes of recent trials (figure 4) highlight the need for precision immunomodulation informed by genetics (TOLLIP, IL1RN, TLR3), immune readouts (monocyte counts, IFN-I signatures) and spatial-omic mappings [23, 56]. Reliance on acute models such as bleomycin remains a limitation; progressive nonresolving models that better reflect human disease are needed.

Several gaps remain. First, the functional consequences of most immune-associated polymorphisms are inferred rather than proven; clustered regularly interspaced short palindromic repeats-engineered induced pluripotent stem cell models offer an opportunity to test variant-specific immune phenotypes. Second, temporal mapping of immune dynamics across the continuum from acute injury to established fibrosis is still limited; longitudinal bronchoscopy, although limited by feasibility, and blood-based multi-omic studies will be key to defining stage-specific therapeutic windows. Third, reproducible biomarkers that predict response to targeted immunotherapy remain scarce; promising candidates include BALF CCL18, serum BAFF, autoantibody repertoires and fibroblast inflammatory state signatures.

At the transcriptomic level, Herazo-Maya et al. [213] identified a 52-gene peripheral blood signature that robustly stratified transplant-free survival in IPF across multiple independent cohorts. This signature is enriched for the “costimulatory signal during T-cell activation” Biocarta pathway, including key genes such as CD28, ICOS (inducible T-cell costimulator), LCK (lymphocyte-specific protein tyrosine kinase) and ITK (IL-2–inducible T-cell kinase), underscoring the tight link between systemic adaptive immune activation and clinical outcome. A subsequent Lancet Respiratory Medicine study validated the high-risk 52-gene profile in additional IPF and non-IPF cohorts, confirming its association with worse prognosis and illustrating how composite immune signatures can serve as prototypical endotypes for fibrotic ILD [214]. Incorporating such blood-based gene expression signatures into future trials may help align mechanism-targeted immunotherapies with patients in whom adaptive immune dysregulation is a dominant driver of progression.

Clinically, stratified trial designs that enrol by immune endotype rather than radiographic pattern will be pivotal. The genotype-guided PRECISIONS study of inhaled N-acetyl-cysteine in TOLLIP risk allele carriers exemplifies this precision framework [177]. Combination regimens pairing antifibrotics with pathway-specific immunomodulators (e.g. Janus kinase inhibitors, anti-BAFF antibodies, CCR2 antagonists) should be tested in adaptive platforms that allow parallel evaluation and rapid refinement.

In summary, viewing the immune system as both trigger and perpetuator reframes therapy toward selective rebalancing of dysregulated pathways. Lessons from past and ongoing trials now enable translation of immune-genetic and spatial-omic discoveries into personalised, endotype-matched interventions. Such strategies hold the promise of transforming current disease-slowing care into truly disease-modifying therapies across the fibrotic ILD spectrum.

Points for clinical practice

• The immune system is involved as both a trigger and a perpetuator of PF.

• At present, antifibrotic therapy is the cornerstone of treatment.

• In the future, pathway-specific immunomodulators may be added in a personalised manner, guided by patient-specific immune endotypes.

Questions for future research

• How do immune mechanisms differ between fibrotic ILD subtypes and disease stages?

• Which biomarkers or immune signatures can stratify patients for targeted interventions?

• Can combining antifibrotics with immune-directed therapies safely improve long-term outcomes?

• Which models best capture progressive, nonresolving fibrosis to test such strategies?