Multifactorial sheltering in peristromal niches shapes in vivo responses of lung cancers to targeted therapies.

Targeted therapies induce strong clinical responses but fail to eliminate advanced cancers, as a subset of tumor cells survives within residual disease and eventually develops resistance. While numerous cell-intrinsic and microenvironmental mechanisms have been implicated in this survival, their relative contributions remain poorly defined. Using spatial histological inferences from ALK + NSCLC models, we show that peristromal niches protect tumor cells from elimination, enabling in vivo persistence. This spatially restricted sheltering provides an ecological rescue mechanism that sustains residual populations, enabling their eventual evolutionary escape. Mechanistically, this protective effect reflects an integrated action of multiple juxtacrine and paracrine signals. This complexity limits the utility of targeting individual mechanisms of protection, favoring a shift towards exploiting orthogonal collateral sensitivities of residual disease. We find that adaptive HER2 upregulation, associated with both cell-intrinsic and stroma-mediated persistence, can be exploited by the antibody-drug conjugate T-DXd to dramatically enhance therapeutic responses and suppress tumor relapse.