Idiopathic pulmonary fibrosis (IPF) is defined by recurrent alveolar injury, failed epithelial regeneration, and progressive scarring of functional lung tissue. Broad immunosuppression worsens outcomes in IPF, yet selected immune states remain integral to disease biology. Human single-cell and spatial studies now identify reproducible immune states within transitional epithelial regions, fibroblastic foci, remodeled airspaces, and lymphoid aggregates, while lineage-resolved experiments show that selected immune populations can alter epithelial fate, fibroblast activation, matrix turnover, and fibrosis resolution. Here, we integrate these findings through four linked variables: developmental origin, acquired state, spatial location, and disease stage. The strongest evidence centers on monocyte-derived alveolar macrophages that persist in injured alveoli and acquire secreted phosphoprotein 1 (SPP1), triggering receptor expressed on myeloid cells 2 (TREM2), MER proto-oncogene tyrosine kinase (MERTK), galectin-3, lipid, and lysosome associated programs. Neutrophils, dendritic cells, mast cells, innate lymphoid cells, T cells, natural killer cells, B cells, and plasma cells contribute with greater context dependence and, in several cases, opposing functions during injury and repair. We also distinguish human association from experimental causation and clinical efficacy, including the failure of phase III zinpentraxin alfa and phase IIb GB0139 despite encouraging early studies. These data support a precision immunology strategy in which a defined pathogenic cell state or intercellular circuit is targeted in a biomarker-selected patient population while host defense, immune surveillance, and reparative immunity are preserved.
