This research communication reports that mice with mosaic deletion of Atg5 and liver-specific Atg7−/− develop benign liver tumors. These tumors originate from autophagy-deficient hepatocytes and exhibit mitochondrial swelling, p62 accumulation, oxidative stress, and genomic damage responses. The size of the tumors is reduced by simultaneous deletion of p62. These findings suggest that autophagy is crucial for suppressing spontaneous tumorigenesis through a cell-intrinsic mechanism, particularly in the liver, and that p62 accumulation contributes to tumor progression. The study also highlights the importance of autophagy in maintaining liver health and preventing tumor development.This research communication reports that mice with mosaic deletion of Atg5 and liver-specific Atg7−/− develop benign liver tumors. These tumors originate from autophagy-deficient hepatocytes and exhibit mitochondrial swelling, p62 accumulation, oxidative stress, and genomic damage responses. The size of the tumors is reduced by simultaneous deletion of p62. These findings suggest that autophagy is crucial for suppressing spontaneous tumorigenesis through a cell-intrinsic mechanism, particularly in the liver, and that p62 accumulation contributes to tumor progression. The study also highlights the importance of autophagy in maintaining liver health and preventing tumor development.