Early fibrotic niches establish tumour-permissive microenvironments.

Pathologictransformationrepresentsa criticalyet poorly defined windowduring whichmutantepithelial stem cellsactivelyconstructthemicroenvironmentthatenablestumour initiation1,2.Here,usingintegratedsingle-cell, spatial, and functional analyses, wedefinethe earliestmulticellular eventsthatlicensethis transition following oncogenic activation in the lung.KrasG12D-mutantalveolar type II cellsrapidlyadoptregenerative-likestatesthatactassignalling hubs,orchestratingcoordinated stromal and immune reprogrammingwhileenhancingepithelial plasticity.Through secretion ofAmphiregulin (Areg),mutant epithelialcellsactivateEGFR signalling in adjacent fibroblasts,inducinga fibrotic, injury-likeprogramme.Reprogrammed fibroblasts, in turn,expand and reprogrammealveolarmacrophages,amplifyinginflammatory signalling andreinforcingepithelial plasticity.Thesereciprocalinteractionsestablisha self-sustaining epithelial–stromal–immunecircuitthatgeneratesatumour-permissive nicheprior tomalignant outgrowth.Disruption oftheAreg–EGFR axispreventsearlynicheformationand abrogatestumourinitiation.Conservation ofthis programme inKRASG12D-induciblehumanalveolar organoidsandearly-stagelungadenocarcinomatissuesidentifiesepithelial–microenvironmentcommunicationasatherapeutically actionable vulnerability and suggests that intercepting niche formation mayprevent progression to treatment-resistant disease