Failure of morphogenesis in chronic inflammation-associated early tumourigenesis: Extracellular matrix biomechanics...

Chronic inflammation promotes tumourigenesis through both mutation accumulation and persistent failure of tissue repair mechanisms to restore organised three-dimensional architecture. However, current frameworks of inflammation-associated tumourigenesis often treat fibrosis, repair failure, immune dysfunction, and tissue disorganisation as parallel processes, without adequately explaining how they become mechanistically linked across biological scales or why repair can remain active while tissue-level order continues to deteriorate. We aimed to develop a conceptual framework that integrates these processes and clarifies how chronic inflammation acquires early tumourigenic potential. This review synthesised evidence from studies of chronic inflammation, extracellular matrix (ECM) biology, mechanobiology, tumour microenvironments, and developmental biology. The literature was analysed to identify common mechanisms linking repair failure, ECM remodelling, multicellular organisation, and precancerous tissue states. The review introduces the concept of failure of morphogenesis as a synthesis framework describing the persistent uncoupling of repair from tissue-level reorganisation. Within this framework, ECM biomechanics functions as a context-dependent integrative layer through which altered matrix mechanics propagate and stabilise precancerous disorder across five interconnected microenvironmental dimensions: mechanical change, immune restructuring, hypoxic amplification, mechanometabolic adaptation, and epigenetic persistence. Transferable physical principles from developmental biology further suggest mechanisms by which ECM-dependent disorder may become spatially organised and mechanically stabilised in chronically inflamed tissues. These findings suggest that precancerous lesions should be understood not only as mutation-bearing abnormalities but also as local manifestations of a broader self-reinforcing tissue condition. This review reframes the transition from chronic inflammation to cancer as extending beyond genetic damage alone to encompass tissue organisation.