TP53 mutations abrogate the control function in cell division, driving oncogenesis and tumor progression. The gene of TP53, known as the "Guardian of the genome and maintains genomic stability by regulating the cell cycle, apoptosis, and DNA repair at key checkpoints. Increasing evidence also suggests that TP53 mutations alter the tumor microenvironment, promoting vascular endothelial growth factor (VEGF)-driven angiogenesis and impairing both innate and adaptive immune responses in cancer cells. These observations provide a rationale for considering angiogenesis, CD47, and immune evasion as therapeutic targets in p53-mutated tumors. In this review, we propose a conceptual nanoparticle-based strategy designed to address both processes with particular emphasis on the CD47–SIRPα axis and VEGF signaling. A ligand-coated nanoparticle can deliver nanoparticles into cancer cells through a ligand-receptor binding site and minimize off target. Another cell component is the surface protein CD47—a prominent "don't eat me" signal—to evade macrophage-mediated phagocytosis. By integrating molecular biology, molecular docking, and nanotechnology, this integrated framework delineates a new era of multi-targeted immunotherapy to overcome therapeutic resistance in p53-mutated malignancies.