p53 mutations are common in many cancers and hinder cancer therapy by promoting resistance to apoptosis and cell cycle arrest, contributing to multidrug resistance. Recent studies highlight p53's immunomodulatory functions, though they are less appreciated than its other roles. This review summarizes the latest research on immune evasion in p53-mutant tumors and explores targeting p53 to enhance anti-tumor immunity. p53 mutations lead to immune evasion by altering antigen presentation, modulating immune checkpoints, and reshaping the tumor microenvironment (TME). Mutant tumor cells recruit immunosuppressive cells like macrophages and Tregs, fostering immunosuppression. Clinical evidence shows p53-mutant cancers respond poorly to immunotherapy. Therapeutic strategies include p53-activating agents, STING agonists, gene therapies, and immune-based therapies to enhance immune response. Combining these with immunotherapy may improve outcomes for p53-mutant cancers. Despite challenges, ongoing research aims to develop effective treatments for these difficult-to-treat cancers.p53 mutations are common in many cancers and hinder cancer therapy by promoting resistance to apoptosis and cell cycle arrest, contributing to multidrug resistance. Recent studies highlight p53's immunomodulatory functions, though they are less appreciated than its other roles. This review summarizes the latest research on immune evasion in p53-mutant tumors and explores targeting p53 to enhance anti-tumor immunity. p53 mutations lead to immune evasion by altering antigen presentation, modulating immune checkpoints, and reshaping the tumor microenvironment (TME). Mutant tumor cells recruit immunosuppressive cells like macrophages and Tregs, fostering immunosuppression. Clinical evidence shows p53-mutant cancers respond poorly to immunotherapy. Therapeutic strategies include p53-activating agents, STING agonists, gene therapies, and immune-based therapies to enhance immune response. Combining these with immunotherapy may improve outcomes for p53-mutant cancers. Despite challenges, ongoing research aims to develop effective treatments for these difficult-to-treat cancers.