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mTORC1 suppression by Trp53 mutation drives resistance to immune checkpoint blockade

Alireza Labani-Motlagh1, Yang Li2, David Shihong Gao2

  • 1Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA.

Cell Death & Disease
|July 6, 2026
PubMed

Insights

Deleting the Trp53 gene enhances anti-PD-1 immunotherapy responses by increasing CD8+ T cell infiltration and reducing regulatory T cells. This involves downregulating mTORC1 inhibitors, diminishing autophagy, and sensitizing tumors to apoptosis.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • The tumor suppressor p53 plays a crucial role in cancer development.
  • TP53 mutations have yielded inconsistent results in cancer immunotherapy.
  • Tumor mutational burden and specific p53 mutant functions influence immunotherapy outcomes.

Purpose of the Study:

  • To investigate the function of G242V and S258I Trp53 mutations in MC38 cells within the context of immunotherapy.
  • To assess the impact of Trp53 deletion on anti-PD-1 therapy response.
  • To elucidate the underlying mechanisms by which p53 mutations affect immunotherapy.

Main Methods:

  • Generated Trp53 deletion in MC38 mouse cells.
  • Assessed tumor responses to anti-PD-1 therapy.
  • Analyzed CD8+ T cell infiltration, regulatory T (Treg) cells, mTORC1 signaling, and autophagy.
  • Confirmed findings in a human colorectal cancer cell line.

Main Results:

  • Trp53 deletion significantly enhanced responses to anti-PD-1 therapy.
  • Trp53-null tumors exhibited increased CD8+ T cell infiltration and clonal expansion, with reduced Treg cells.
  • Trp53 deletion downregulated mTORC1 inhibitor genes, elevated mTORC1 signaling, diminished autophagy, and sensitized tumor cells to IFN-γ and TNF-α-induced apoptosis.
  • Human p53 mutants regulated the same mTORC1 inhibitor genes as observed in mouse cells.

Conclusions:

  • Certain p53 mutants retain the ability to suppress mTORC1 and enhance autophagy, inhibiting immunotherapy responses.
  • Trp53 deletion sensitizes tumors to immunotherapy by modulating the tumor microenvironment and cellular signaling pathways.
  • Understanding the role of p53 mutants in immunotherapy is critical for developing effective cancer treatments.

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