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

TL;DR

This study shows that a specific TP53 mutation in prostate cancer can make tumors more responsive to immunotherapy by changing the tumor environment to attract immune cells.

Contribution

The study reveals a novel mechanism by which mutant p53 enhances anti-PD-1 therapy response through epigenetic regulation of CXCL10 and immune remodeling.

Findings

Mutant p53 promotes CD8⁺ T-cell infiltration and anti-PD-1 sensitivity by upregulating CXCL10.

Mutant p53 epigenetically rewires the tumor microenvironment to reduce cancer-associated fibroblasts and support immune activation.

CXCL10 expression correlates with immune activation and clinical benefit from immunotherapy in patient cohorts.

Abstract

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.

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.

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.

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.

The online version contains supplementary material available at 10.1186/s13046-026-03672-z.

Mutp53 tumors exhibit heightened sensitivity to anti–PD-1 therapy.

Epithelial-derived CXCL10 recruits activated CD8+ T cells via CXCR3.

Mutp53 occupies the CXCL10 promoter and remodels histone marks to boost transcription.

Mutp53 reduces CAF barriers and fosters an immune-permissive tumor microenvironment.

The online version contains supplementary material available at 10.1186/s13046-026-03672-z.

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