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Background <p><i>TP53</i> mutations are frequently linked to an immunosuppressive tumor microenvironment and resistance to immune checkpoint blockade (ICB). However, their mechanistic role in shaping antitumor immunity in advanced prostate cancer remains unclear.</p> Methods <p>We generated CRISPR-Cas9-engineered murine prostate cancer models harboring the <i>Trp53</i> p.R245Q knock-in mutation (orthologous to human <i>TP53</i> p.R248Q). Tumor growth and response to anti-PD-1 therapy were evaluated in vivo. Single-cell RNA sequencing and integrated immune profiling were performed to characterize stromal and immune remodeling. Chromatin immunoprecipitation assays were used to assess mutant p53 binding and histone modifications at the <i>Cxcl10</i> promoter. Statistical significance was assessed using Student’s t-test, Wilcoxon rank-sum test, and one-/two-way ANOVA, as appropriate.</p> Results <p>Mutant p53 accelerated tumor progression yet unexpectedly enhanced responsiveness to anti-PD-1 therapy within an otherwise suppressive microenvironment. Single-cell transcriptomics revealed epithelial lineage and metabolic rewiring, accompanied by depletion of cancer-associated fibroblasts and a shift toward immune-permissive stromal states. Immune profiling demonstrated increased infiltration of cytotoxic CD8⁺ granzyme B⁺ T cells and augmented lymphoid and vascular features. Mechanistically, mutant p53 occupied the <i>Cxcl10</i> promoter, remodeled local chromatin by enriching H3K4me3 while reducing repressive histone marks, and transcriptionally upregulated <i>Cxcl10</i>. This established a CXCL10–CXCR3 chemotactic axis that promoted recruitment of cytotoxic CD8⁺ T cells and sensitized tumors to PD-1 blockade. Consistently, cohort analysis further supported that high CXCL10 expression correlated with immune activation and clinical benefit from ICB.</p> Conclusions <p>These findings indicate that mutant p53 can reprogram immune-cold prostate tumors into immune-hot ecosystems through coordinated epigenetic, metabolic, and stromal-immune remodeling. <i>TP53</i> mutation status may therefore inform patient stratification and combinatorial immunotherapeutic strategies targeting the CXCL10–CXCR3 axis.</p>

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Mutant p53 epigenetically rewires CXCL10 to promote CD8⁺ T-cell infiltration and enhance the anti-PD-1 response in advanced prostate cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月3日

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  • Jia Chen,
  • Qintao Ge,
  • Jun He,
  • Zichen Bian,
  • Haoming Yu,
  • Chun Li,
  • Jialin Meng,
  • Shuiping Yin,
  • Zongyao Hao,
  • Chaozhao Liang,
  • Meng Zhang

摘要

Background

TP53 mutations are frequently linked to an immunosuppressive tumor microenvironment and resistance to immune checkpoint blockade (ICB). However, their mechanistic role in shaping antitumor immunity in advanced prostate cancer remains unclear.

Methods

We generated CRISPR-Cas9-engineered murine prostate cancer models harboring the Trp53 p.R245Q knock-in mutation (orthologous to human TP53 p.R248Q). Tumor growth and response to anti-PD-1 therapy were evaluated in vivo. Single-cell RNA sequencing and integrated immune profiling were performed to characterize stromal and immune remodeling. Chromatin immunoprecipitation assays were used to assess mutant p53 binding and histone modifications at the Cxcl10 promoter. Statistical significance was assessed using Student’s t-test, Wilcoxon rank-sum test, and one-/two-way ANOVA, as appropriate.

Results

Mutant p53 accelerated tumor progression yet unexpectedly enhanced responsiveness to anti-PD-1 therapy within an otherwise suppressive microenvironment. Single-cell transcriptomics revealed epithelial lineage and metabolic rewiring, accompanied by depletion of cancer-associated fibroblasts and a shift toward immune-permissive stromal states. Immune profiling demonstrated increased infiltration of cytotoxic CD8⁺ granzyme B⁺ T cells and augmented lymphoid and vascular features. Mechanistically, mutant p53 occupied the Cxcl10 promoter, remodeled local chromatin by enriching H3K4me3 while reducing repressive histone marks, and transcriptionally upregulated Cxcl10. This established a CXCL10–CXCR3 chemotactic axis that promoted recruitment of cytotoxic CD8⁺ T cells and sensitized tumors to PD-1 blockade. Consistently, cohort analysis further supported that high CXCL10 expression correlated with immune activation and clinical benefit from ICB.

Conclusions

These findings indicate that mutant p53 can reprogram immune-cold prostate tumors into immune-hot ecosystems through coordinated epigenetic, metabolic, and stromal-immune remodeling. TP53 mutation status may therefore inform patient stratification and combinatorial immunotherapeutic strategies targeting the CXCL10–CXCR3 axis.