Intratumoral Hippo heterogeneity confers symbiotic communications to resist ferroptosis

The stress of the tumor microenvironment constitutes tumor heterogeneity. However, the complex mechanisms by which symbiosis is maintained between subclones that persist heterogeneity in tumors remain unclear. Here, We demonstrated that in the mouse lung cancer model, the deletion of the effector YAP/TAZ of the Hippo pathway not only produced lipid peroxidation resistance on its own, but also that this lipid peroxidation resistance could be transmitted to adjacent cells. Mechanistically, YAP/TAZ inhibits the transcriptional state of GCH1 chromatin, while the loss of YAP/TAZ activates GCH1 overexpression and maintains the lipid peroxidation resistance of Hippo heterogeneous tumors through the transfer of its metabolite BH4 between adjacent cells. Our study uncover the key role of Hippo heterogeneity in tumor progression and demonstrates the possibility of inhibiting symbiosis as a tumor treatment.