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p53 hotspot mutants attenuate CTL-mediated tumor cell killing through a novel ALKBH5-YTHDF3-PD-L1 pathway

Zhuan Ju1,2,3,4, Xiang Zhang3, Wenjie Zuo2

  • 1State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.

Oncogene
|July 30, 2026
PubMed

Insights

Gain-of-function mutant p53 promotes cancer by increasing PD-L1 expression via the m6A-YTHDF3 pathway, hindering anti-tumor immunity. Restoring ALKBH5 reactivates immune surveillance against mutant p53 tumors.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • TP53 mutations are common in cancer, with gain-of-function (GOF) mutations promoting tumor progression.
  • The precise mechanisms by which mutant p53 drives cancer, particularly its interaction with the tumor immune microenvironment, remain unclear.

Purpose of the Study:

  • To elucidate the extrinsic oncogenic mechanisms of GOF mutant p53.
  • To investigate the role of mutant p53 in regulating the tumor immune microenvironment and PD-L1 expression.

Main Methods:

  • In vivo and in vitro studies involving mutant p53 expressing cells.
  • Analysis of PD-L1 expression, N6-methyladenosine (m6A) modification, and the role of YTHDF3 and ALKBH5.
  • Assessment of anti-tumor immune responses mediated by cytotoxic T lymphocytes (CTLs).

Main Results:

  • Mutant p53 expression significantly increases PD-L1 levels in cancer cells.
  • PD-L1 mRNA stability and translation are regulated by m6A modification and the reader protein YTHDF3.
  • Mutant p53 inhibits ALKBH5, leading to m6A-YTHDF3-mediated PD-L1 upregulation and immune evasion.
  • Restoring ALKBH5 suppresses PD-L1, enhances CTL responses, and inhibits tumor growth.

Conclusions:

  • Mutant p53 potentiates cancer immune evasion through the ALKBH5-m6A-YTHDF3-PD-L1 axis.
  • Restoring ALKBH5 or inhibiting the m6A-YTHDF3 pathway represents a potential therapeutic strategy for mutant p53-driven tumors.
  • Targeting this pathway could reactivate immune surveillance and eliminate tumors harboring mutant p53.

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