Inflammatory myofibroblastic tumour: unravelling the interplay of inflammation, kinase signalling, and therapeutic resistance.

Inflammatory myofibroblastic tumour (IMT) is a mesenchymal tumour characterised by myofibroblastic cells and the presence of inflammatory cells, such as macrophages, neutrophils, and lymphocytes. IMT can originate from diverse anatomical locations within the body. The macrophage-rich immune microenvironment contributes to cytokine release and inflammation, but IMT is primarily driven by oncogenic alterations. Oncogenic fusions, most commonly involving anaplastic lymphoma kinase (ALK), and other genes, such as ROS1 and NTRK3, are seen in most IMTs. Upregulation of these genes activates downstream signalling pathways such as RAS/MAPK and PI3K/AKT, leading to uncontrolled cell proliferation. Constitutive tyrosine kinase activation disrupts cell-cycle control by suppressing p21/p27, inactivating Rb, and impairing p53-dependent checkpoints, thereby limiting apoptosis. Combining surgery with targeted kinase inhibitors remains the primary therapeutic approach, especially for ALK-positive IMT. On the contrary, ALK-negative IMT harbours distinct oncogenic fusions and is driven by diverse signalling pathways. Thus, it requires therapeutic methods targeting the specific molecular alterations. Resistance to ALK inhibitors can emerge during treatment. This resistance arises through bypass signalling, epigenetic changes, and secondary mutations. This review aims to analyse the interplay between inflammation and genetic fusions in the origin and progression of IMT. The review provides an overview of the therapeutic approaches currently in use, mechanisms of treatment resistance, and potential techniques to improve diagnosis and develop personalised therapeutic strategies.