This study investigates the role of p53 acetylation in tumor suppression. The authors generated mice with lysine-to-arginine mutations at one (p53K117R) or three (p53KR; K117R-K161R-K162R) of the critical p53 acetylation sites. While p53K117R/K117R cells retained p53-mediated cell-cycle arrest and senescence but not apoptosis, all three processes were abrogated in p53KR/KR cells. Surprisingly, neither p53K117R/K117R nor p53KR/KR mice developed early-onset tumors, unlike p53-null mice. Notably, p53KR retained the ability to modulate energy metabolism and reactive oxygen species (ROS) production by regulating metabolic p53 target genes. These findings suggest that unconventional activities of p53, such as metabolic regulation and antioxidant function, are critical for suppressing early-onset spontaneous tumorigenesis.This study investigates the role of p53 acetylation in tumor suppression. The authors generated mice with lysine-to-arginine mutations at one (p53K117R) or three (p53KR; K117R-K161R-K162R) of the critical p53 acetylation sites. While p53K117R/K117R cells retained p53-mediated cell-cycle arrest and senescence but not apoptosis, all three processes were abrogated in p53KR/KR cells. Surprisingly, neither p53K117R/K117R nor p53KR/KR mice developed early-onset tumors, unlike p53-null mice. Notably, p53KR retained the ability to modulate energy metabolism and reactive oxygen species (ROS) production by regulating metabolic p53 target genes. These findings suggest that unconventional activities of p53, such as metabolic regulation and antioxidant function, are critical for suppressing early-onset spontaneous tumorigenesis.