Immunological mechanisms and therapeutic approaches in pulmonary fibrosis.

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.