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

Sep 21, 2026

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p53 is a key tumor suppressor protein encoded by the frequently mutated gene TP53 in human cancers. As a well-known transcription factor, p53 orchestrates core cellular programs from cell-cycle arrest and DNA repair to senescence and programmed cell death (PCD), including autophagy, apoptosis, ferroptosis, cuproptosis, pyroptosis, and disulfidoptosis. Tumor progression depends on crosstalk among the tumor microenvironment (TME), N6-methyladenosine (m6A) RNA modification, and diverse PCD pathways. The review systematically summarizes p53 functions across TME regulation, m6A-mediated control, and multiple PCD mechanisms, highlighting implications for novel therapeutic strategies.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages22

Reading Time55 min

AccessFree to download

Introduction

The tumor microenvironment

Understanding the tumor microenvironment (TME)

The regulation of tumor microenvironment and immune response by p53

N6-Methyladenosine (m6A) modification

The key role of m6A modification in RNA biology

The impact of m6A modification on p53 and its role in cancer

Regulatory role of p53 in m6A RNA methylation

Journal of Advanced Research 75 (2025) 539–560 Contents lists available at ScienceDirect Journal of Advanced Research journal [homepage: www. elsevier. com/locate/jare](homepage: www. elsevier. com/locate/jare) Multiple roles of p53 in cancer development: Regulation of tumor microenvironment, m6A modiﬁcation and diverse cell death mechanisms Xiangyu Wang a, Jianhua Yang b, Wanting Yang a, Haiyang Sheng c, Buyun Jia a, Peng Cheng d, Shanshan Xu Xinhui Hong a, Chuanwei Jiang a, Yinfeng Yang b, ⇑, Ziyin Wu e, ⇑, Jinghui Wang a, ⇑ a School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, China b School of Medical Informatics Engineering, Anhui University of Chinese Medicine, Hefei, Anhui, China c Global Biometrics and Data Sciences, Bristol Myers Squibb, New York City, USA d The First Afﬁliated Hospital, Anhui University of Traditional Chinese Medicine, Hefei, Anhui, China e State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Jiangsu Kanion Pharmaceutical Co. Ltd, Lianyungang, Jiangsu, China a , h i g h l i g h t s 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. g r a p h i c a l a b s t r a c t a r t i c l e i n f o Article history: Received 16 July 2024 Revised 2 October 2024 Accepted 23 October 2024 Available online 28 October 2024 Keywords: p53 Tumor suppression Tumor microenvironment M6A a b s t r a c t Background: 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, pyroptosisand disulﬁdoptosis. Accumulating evidence has indicated that the tumor microenvironment (TME), N6-methyladenosine (m6A) modiﬁcation and diverse PCD are important for the progression, proliferation and metastases of cancers. Aim of review: This paper aims to systematically and comprehensively summarize the multiple roles of p53 in the development of cancers from the regulation of TME, m6A Modiﬁcation and diverse PCD. Key scientiﬁc concepts of review: TME, a crucial local homeostasis environment, inﬂuences every step of ⇑ Corresponding authors. E-mail [addresses:](addresses: yinfengyang@yeah.net)[ yinfengyang@yeah.net](addresses: yinfengyang@yeah.net) (Y. Yang), [wzy1903@kanion.com](wzy1903@kanion.com) (Z. Wu), [jhwang_dlut@163.com](jhwang_dlut@163.com) (J. Wang). [https://doi.org/10.1016/j.jare.2024.10.026](https://doi.org/10.1016/j.jare.2024.10.026) 2090-1232/© 2024 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)). X. Wang, J. Yang, W. Yang et al. Programmed cell death Journal of Advanced Research 75 (2025) 539–560 tumorigenesis and metastasis. m6A, 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 suic

FAQs

What are the major cellular functions governed by p53 in cancer biology?

p53 regulates cell-cycle arrest, DNA repair, senescence, and programmed cell death (PCD) pathways including autophagy, apoptosis, ferroptosis, cuproptosis, pyroptosis, and disulfidoptosis.

How does the tumor microenvironment (TME) interact with p53 during cancer development?

The review describes p53 as a regulator of the TME and its immune-related responses, showing how p53 influences pathways in the microenvironment that affect cancer progression.

What is the relationship between p53 and m6A RNA modification?

The paper summarizes how m6A modification connects to p53 biology, including how m6A impacts p53 and how p53 can regulate m6A RNA methylation, contributing to cancer development.

Sep 21, 2026

Uploaded by Ophelia