Multiple roles of p53 in cancer development: Regulation of tumor microenvironment, m6A modification and diverse cell death mechanisms

• Multifaceted Role of p53 in Cancer: Investigating p53’s functions in cancer biology and its impact on tumor progression and treatment. • Interactions in the Tumor Microenvironment: Examining p53’s role with various cell types and pathways in the TME affecting cancer. • p53 and m6A Modification: Exploring the link between p53 and m6A RNA modification and its implications for cancer. • p53 Regulation of Cell Death Mechanisms: Identifying p53’s role in autophagy, ferroptosis, and other cell death pathways. • Therapeutic Implications: Exploring potential targets based on p53’s roles and contributions to personalized cancer treatments. The protein p53, encoded by the most frequently mutated gene TP53 in human cancers, has diverse functions in tumor suppression. As a best known transcription factor, p53 can regulate various fundamental cellular responses, ranging from the cell-cycle arrest, DNA repair, senescence to the programmed cell death (PCD), which includes autophagy, apoptosis, ferroptosis, cuproptosis, pyroptosis and disulfidoptosis. Accumulating evidence has indicated that the tumor microenvironment (TME), N 6 -methyladenosine (m 6 A) modification and diverse PCD are important for the progression, proliferation and metastases of cancers. This paper aims to systematically and comprehensively summarize the multiple roles of p53 in the development of cancers from the regulation of TME, m 6 A Modification and diverse PCD. TME, a crucial local homeostasis environment, influences every step of tumorigenesis and metastasis. m 6 A, the most prevalent and abundant endogenous modification in eukaryotic RNAs, plays an essential role in various biological processes, containing the progression of cancers. Additionally, PCD is an evolutionarily conserved mechanism of cell suicide and a common process in living organisms. Some forms of PCD contribute to the occurrence and development of cancer. However, the complex roles of p53 within the TME, m 6 A modification and diverse PCD mechanisms are still not completely understood. Presently, the function roles of p53 including the wild-type and mutant p53 in different context are summarized. Additionally, the interaction between the cancer immunity, cancer cell death and RNA m 6 A methylation and the p53 regulation during the development and progress of cancers were discussed. Moreover, the key molecular mechanisms by which p53 participates in the regulation of TME, m 6 A and diverse PCD are also explored. All the findings will facilitate the development of novel therapeutic approaches.