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Modulating the Immunosuppressive Tumor Microenvironment and Inhibiting Growth in Mutp53-Driven CRPC via STAT3 Pathway

Zichen Bian1, Jia Chen1, Yufan Wang1

  • 1Department of Urology, The First Affiliated Hospital of Anhui Medical University; Institute of Urology, Anhui Medical University; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei, 230022, China.

International Journal of Biological Sciences
|May 19, 2025
PubMed

Insights

TP53 mutations, especially p.R248Q, drive castration-resistant prostate cancer (CRPC) by creating an immunosuppressive tumor microenvironment (TME). Targeting the STAT3 pathway with inhibitors can reduce this immune suppression and slow CRPC progression.

Area of Science:

  • Oncology
  • Cancer Biology
  • Immunology

Background:

  • TP53 mutations are implicated in cancer progression, including prostate cancer.
  • The p.R248Q variant of TP53 is frequently observed in prostate cancer patients.
  • Understanding the role of mutant p53 (mutp53) in the tumor microenvironment (TME) is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate the impact of the TP53 p.R248Q mutation on immune suppression and castration-resistant prostate cancer (CRPC) progression.
  • To elucidate the underlying mechanisms involving the IL6/JAK2/STAT3 pathway.
  • To evaluate the therapeutic potential of targeting this pathway in CRPC.

Main Methods:

  • CRISPR/Cas9 gene editing to introduce Trp53 p.R245Q mutation in mouse prostate cancer cells, mimicking human TP53 p.R248Q.
  • Implantation of gene-edited cells into C57BL/6 mice to model CRPC progression and immune interactions.
  • Treatment with JAK2 and STAT3 inhibitors, followed by analysis using histology, immunofluorescence, flow cytometry, ELISA, and bioinformatics.
  • Validation in the C4-2 human prostate cancer cell line.

Main Results:

  • TP53 mutations, particularly p.R248Q, were associated with reduced overall and recurrence-free survival in prostate cancer patients.
  • Gene-edited mutp53 cells showed increased proliferation and tumorigenicity.
  • Mutp53 tumors exhibited activation of the IL6/JAK2/STAT3 pathway, leading to an immunosuppressive TME with decreased pro-inflammatory and increased anti-inflammatory cytokines.
  • Mutp53 was found to compete with SHP1 for STAT3 binding, sustaining STAT3 activation.
  • STAT3 inhibition effectively reduced mutp53-driven immune suppression and tumor progression.

Conclusions:

  • Mutant TP53, specifically the p.R248Q variant, promotes an immunosuppressive TME that facilitates CRPC progression.
  • The IL6/JAK2/STAT3 signaling pathway is a key mediator of mutp53-driven immune evasion and tumor growth.
  • Targeting the STAT3 pathway represents a promising therapeutic strategy for CRPC harboring TP53 mutations.
Keywords:
STAT3 signalingTP53castration-resistant prostate cancerimmune-suppressed microenvironmentp.R248Q

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