In the tumor stroma, cancer-associated fibroblasts (CAFs) affect all aspects of tumor evolution. Whereas several programs leading to CAF activation have been elucidated, little is known about the impact of the microenvironment on the turnover of key CAF regulators. RBPJ/CSL is a transcriptional repressor that mediates NOTCH signaling and its down-modulation activates the gene expression program(s) leading to stromal senescence and CAF activation. We overview our evidence that conditions increasing macroautophagy/autophagy, as often found in the stroma of tumors, cause the down-modulation of the RBPJ protein. This event requires the autophagic machinery and is functionally relevant because it is associated with an increase of CAF effector gene expression. The mechanism involves the direct association with the autophagy receptor SQSTM1/p62, which is required for RBPJ down-modulation. As a reflection of increased autophagy in the stroma, both the RBPJ and SQSTM1 proteins are down-modulated in Squamous Cell Carcinoma (SCC) patient-derived CAFs. Increasing RBPJ cellular levels stabilizes SQSTM1 and down-modulates the autophagic process. Our findings identify an autophagy-initiated mechanism for RBPJ down-modulation leading to increased CAF gene expression.