The guardian of the genome meets immunotherapy - p53-based strategies

Sep 23, 2026

Uploaded by Angel

The review examines how the p53 “genome guardian” integrates transcriptional control with broader functions in cancer. It explains p53 dysregulation as a major driver of human tumors, including the high prevalence of TP53 mutations and the impact on tumor evolution and antigenicity. It analyzes how p53-generated neoantigens and tumor-associated antigens enable T-cell recognition and evaluates current and emerging p53-targeted immunotherapies, emphasizing immunotherapy platforms and translation challenges.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Introduction

Key aspects of p53 function and regulation

Role of p53 in stress responses and tumor suppression

p53 structure and regulation via post-translational modifications

Relationship between p53 status and tumor evolution

p53-targeted immunotherapeutic platforms and future directions

TYPE Review PUBLISHED 10 March 2026 DOI 10.3389/fimmu.2026.1762679 OPEN ACCESS EDITED BY Nandini Verma, Research and Education in Cancer (ACTREC), India REVIEWED BY Saptak Banerjee, Chittaranjan National Cancer Institute (CNCI), India Suresh Satpati, University of Texas, United States *CORRESPONDENCE Sergey V. Sennikov [sennikovsv@gmail.com](sennikovsv@gmail.com) RECEIVED 07 December 2025 REVISED 12 February 2026 ACCEPTED 23 February 2026 PUBLISHED 10 March 2026 CITATION Savostyanova TA, Lopatnikova JA and Sennikov SV (2026) The guardian of the genome meets immunotherapy: p53-based strategies. Front. Immunol. 17:1762679 . doi: 10.3389/fimmu.2026.1762679 COPYRIGHT © 2026 Savostyanova, Lopatnikova and Sennikov. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. The guardian of the genome meets immunotherapy: p53-based strategies Tatyana A. Savostyanova 1,2, Julia A. Lopatnikova 1 and Sergey V. Sennikov 1,3* 1 Laboratory of Molecular Immunology, Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia, 2 Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia, 3 Institute of Medicine and Medical Technologies, Department of Immunology, Novosibirsk State University, Novosibirsk, Russia Originally reported as an oncogene and currently known to be a major “genome guardian”, the p53 protein remains one of the most explored transcription factors, exhibiting variety of functions both within transcription regulation and beyond. Given that p53 dysfunction contributes to the majority of human cancers, understanding its regulatory mechanisms and therapeutic potential remains a primary research focus. This review addresses the key aspects of p53 regulation and functionality, analyses its role in tumor evolution, and provides a comprehensive analysis of current and emerging therapeutic strategies targeting the p53, with particular emphasis on immunotherapy approaches. KEYWORDS adoptive TCR-T therapy, gene replacement therapy, p53 neoantigens, p53-based vaccines, TP53 mutations, tumor suppressor protein p53 1 Introduction The tumor suppressor protein p53 serves as a central hub in cellular responses to diverse types of stress and prevents malignant transformation through regulation of cell cycle, apoptosis, senescence, DNA repair, and metabolic reprogramming. Dysregulation of the p53 pathway profoundly affects the majority of human cancers, and more than half of tumors are driven by mutations in the TP53 gene. Beyond its traditional cell housekeeping functions, evidence gathered over the past decade has positioned p53 to be involved in antitumor immunity by modulating both innate and adaptive immune responses, regulating the expression of immune checkpoints, and inﬂuencing the immunogenicity of tumor cells. A particularly compelling aspect of p53 biology in the context of cancer immunotherapy arises from its role as a source of tumor-speciﬁc neoantigens caused by TP53 mutations, as well as of tumor-associated antigens generated due to over-accumulation of wild-type p53 in tumor cells, thereby escaping tolerance and enabling T-cell recognition. Unlike private neoantigens, TP53 hotspot mutation landscape (e.g., R175H, Y220C, R273H, G245S) is shared across patients and tumor types, making p53-derived peptides attractive public neoantigens for off-the-shelf immunotherapies. Advances in peptide- and mRNA-based therapeutics and adoptive TCR-engineered T-cell technologies have transformed p53-targeted immunotherapy concepts into clinically re

FAQs

Why is p53 considered a central hub in cellular stress responses and cancer prevention?

p53 coordinates multiple outcomes, including cell-cycle control, apoptosis, senescence, DNA repair, and metabolic reprogramming, which collectively prevent malignant transformation. Dysregulation of the p53 pathway strongly affects most human cancers.

How do TP53 mutations make p53-derived peptides useful for immunotherapy?

TP53 hotspot mutations generate tumor-specific neoantigens that are shared across patients and tumor types, enabling “public” neoantigen targeting. This supports off-the-shelf immunotherapy approaches using peptides and mRNA-based strategies.

What challenges limit the effectiveness of p53-based immunotherapy in clinical responses?

Early-phase trials show safety and antigen-specific T-cell reactivity, but objective tumor responses are infrequent and rarely durable. The review highlights barriers to translating p53-targeted immunotherapy into effective clinical practice.

Sep 23, 2026

Uploaded by Angel