Researchers led by Wang and colleagues reported a ferroptosis-based nanotherapy that selectively targets colorectal cancer–associated fibroblasts (CAFs), reprogramming the tumor microenvironment and reducing stroma-mediated therapy resistance. The nanoparticle induces iron-dependent lipid peroxidation in CAFs, diminishing their pro-tumorigenic signaling. Preclinical models showed stromal remodeling, enhanced drug penetration, and tumor growth suppression when ferroptosis nanotherapy was combined with standard treatments. The strategy targets a non-malignant compartment—CAFs—to indirectly sensitize tumors to therapy. Translation will require careful assessment of selective CAF targeting versus toxicity to normal fibroblasts and tissues. If safety margins hold, stromal-targeted ferroptosis could be incorporated into combination regimens to overcome microenvironmental barriers in colorectal cancer.