When new therapies arrive, we should think more: The unseen challenges of immunotherapy-induced remodeling

Figure 1 Pathogenesis of immune-mediated bowel wall remodeling. Stage 1 (blue): Immune checkpoint inhibition is lifted, activating and infiltrating T cells; stage 2 (orange): Activated T cells and M1-type macrophages release large amounts of interferon-gamma and tumor necrosis factor alpha; stage 3 (green): Fibroblasts are activated and upregulate transforming growth factor beta, initiating the fibrosis program; stage 4 (red): Transforming growth factor beta promotes the deposition of type I/III collagen; simultaneously, inflammatory mediators cause vascular endothelial damage, microthrombosis formation, tissue hypoxia, and impaired angiogenesis; stage 5 (purple): Disordered collagen deposition disrupts the matrix structure, leading to reduced tissue tension and ultimately increased intestinal wall fragility. PD: Programmed death; IFN-γ: Interferon-gamma; TNF-α: Tumor necrosis factor alpha; TGF-β: Transforming growth factor beta.