Significance p53 research has primarily addressed its cell-autonomous tumor-suppressive features. Yet, recent evidence suggests that, in normal tissues, p53 can also exert cell nonautonomous tumor suppressor activities. Cancer-associated fibroblasts (CAFs) enhance the malignant features of adjacent cancer cells. Surprisingly, we found that the conversion of normal fibroblasts to CAFs entails nonmutational alteration of their p53, such that it now becomes cancer supportive rather than cancer inhibitory. This is achieved through reprogramming the transcriptional output of the CAF p53, rendering it a positive regulator of cancer-promoting genes and secreted proteins. Overall, our study highlights a function of nonmutated p53 in the tumor microenvironment and suggests that molecules that can “re-educate” the renegade p53 may have therapeutic value.