Life and Death Decision-Making by p53 and Implications for Cancer Immunotherapy

The tumor-suppressor protein p53 plays a crucial role in cell fate decision-making. Mild and short-term DNA damage leads to p53 activation of pro-survival mechanisms, allowing the cells to repair and recover from the damage. Intensive and prolonged DNA damage triggers p53-dependent cell death to avoid the accumulation of genomic mutations. The life and death decision-making by p53 is influenced by multiple mechanisms, including p53 post-translational modification, different binding affinities for p53 response elements, p53 threshold levels and dynamic patterns, and p53 regulation of miRNAs. Wild-type p53 enhances antitumor immunity by sensitizing cells to immunogenic cell death, whereas mutant p53 increases mutational burden and promotes neoantigenesis. p53-dependent anticancer immunity represents a promising direction for the development of cancer therapeutic strategies. The tumor-suppressor protein p53 is mutated in approximately half of all cancers, whereas the p53 signaling network is perturbed in almost all cancers. In response to different stress stimuli, p53 selectively activates genes to elicit a cell survival or cell death response. How p53 makes the decision between life and death remains a fascinating question and an exciting field of research. Understanding how this decision is made has major implications for improving cancer treatments, particularly in recently evolved immune checkpoint inhibition therapy. We highlight progress and challenges in understanding the mechanisms governing the p53 life and death decision-making process, and discuss how this decision is relevant to immune system regulation. Finally, we discuss how knowledge of the p53 pro-survival and pro-death decision node can be applied to optimize immune checkpoint inhibitor therapy for cancer treatment. The tumor-suppressor protein p53 is mutated in approximately half of all cancers, whereas the p53 signaling network is perturbed in almost all cancers. In response to different stress stimuli, p53 selectively activates genes to elicit a cell survival or cell death response. How p53 makes the decision between life and death remains a fascinating question and an exciting field of research. Understanding how this decision is made has major implications for improving cancer treatments, particularly in recently evolved immune checkpoint inhibition therapy. We highlight progress and challenges in understanding the mechanisms governing the p53 life and death decision-making process, and discuss how this decision is relevant to immune system regulation. Finally, we discuss how knowledge of the p53 pro-survival and pro-death decision node can be applied to optimize immune checkpoint inhibitor therapy for cancer treatment. a form of programmed cell death characterized by caspase activation, nuclear fragmentation, and cell shrinkage. Apoptosis is crucially important for embryo development, metamorphosis, and the removal of unnecessary or damaged cells. an increased tendency towards genomic alterations, including mutation, amplification, or deletion, chromosomal rearrangements, and aneuploidy. Cancer cells are commonly characterized as being genome-instable. a type of cell death through which dying cells release host molecules and DAMPs, which subsequently trigger adaptive immune responses. ICD of cancer cell is an important contributor to some anticancer therapeutic approaches where ICD suppresses cancer progression by releasing TAAs. immune checkpoints are cell-surface proteins that are responsible for the maintenance of immune homeostasis by preventing overactive immune responses, sometimes preventing T cells from killing cancer cells. ICIs are molecules that target and block immune checkpoints.