Tumor relapse after radiotherapy is a big challenge to oncologists. Here, we discovered that cancer-associated fibroblasts (CAFs), a major component of cancer stromal cells, promote cancer cell recovery and tumor relapse postradiation. We provided evidences that CAFs-produced cytokines/chemokines and intermediate metabolites are capable of inducing autophagy in cancer cells post-radiation and promoting cancer cells recovery from radiationinduced damage in vitro and in mice, which was consistent with our clinical observation that the newly developed image-guided stereotactic body radiation therapy (SBRT) was less effective than the conventional external beam radiotherapy (EBRT) in term of recurrence and survival of cancer patients. Mechanistically, CAF-derived cytokines maintained the redox homeostasis post-radiation and increased ROS level compared to control irradiated cancer cells, ROS enhanced the activity of PP2Ac through a reversible sulfenylation on the cysteine residue in the motif of HC (X) 4EXV, similar as the motif of HC (X) 5RS/T in PTPs (protein tyrosine phosphatases), distinct from the sulfenylation of HC (X) 5RS/T motif, which inactivates the activity of PTPs. Moreover, the inhibition of autophagy abolished the CAF-promoted tumor relapse post-radiotherapy. Taken together, our findings demonstrate that CAFs promote cancer cell recovery and tumor regrowth post-radiation, suggesting CAFs are critical for tumor recurrence after radiation and autophagy pathway is a therapeutic target for radiotherapy sensitization.