Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response

The tumor microenvironment (TME) presents cells with challenges such as variable pH, hypoxia, and free radicals, triggering stress responses that affect cancer progression. In this study, we examine the stress response landscape in four carcinomas—breast, pancreas, ovary, and prostate—across five pathways: heat shock, oxidative stress, hypoxia, DNA damage, and unfolded protein stress. Using a combination of experimental and computational methods, we create an atlas of stress responses across various types of carcinomas. We find that stress responses vary within the TME and are especially active near cancer cells. Focusing on the non-immune stroma we find, across tumor types, that NRF2 and the oxidative stress response are distinctly activated in immune-regulatory cancer-associated fibroblasts and in a unique subset of cancer-associated pericytes. Our study thus provides an interactome of stress responses in cancer, offering ways to intersect survival pathways within the tumor, and advance cancer therapy.