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

Mutations in <i>TP53</i>, particularly the p.R248Q variant, contribute to the progression of castration-resistant prostate cancer (CRPC) by reshaping the tumor microenvironment (TME). This study examined the impact of p.R248Q (mutp53) on immune suppression and CRPC progression. We introduced the <i>Trp53</i> p.R245Q mutation into RM-1 mouse prostate cancer (PCa) cells via CRISPR/Cas9, which mimics human <i>TP53</i> p.R248Q. These cells were implanted into C57BL/6 mice to model tumor progression and immune interactions. Mice were treated with JAK2 and STAT3 inhibitors to assess immune and tumor responses. Tumor behavior and immune responses were analyzed via histology, immunofluorescence, flow cytometry, Enzyme-linked immunosorbent assay (ELISA), and bioinformatics. Findings were validated in the C4-2 human PCa cell line. Compared with wild-type p53, <i>TP53</i> mutations were present in 27% of PCa patients and were significantly correlated with reduced overall survival (p < 0.001, HR = 1.97) and recurrence-free survival (p = 0.02, HR = 1.62). The p.R248Q mutation was most prevalent. Gene-edited mutp53 cells exhibited increased proliferation and tumorigenicity. Screening and validation confirmed that IL6/JAK2/STAT3 pathway activation in mutp53 tumors led to immune microenvironment alterations. Flow cytometry and immunofluorescence revealed an immunosuppressive profile, with decreased proinflammatory cytokines and elevated anti-inflammatory factors. Coimmunoprecipitation revealed that mutp53 competes with SHP1 for STAT3 binding, sustaining its activation. Inhibition of STAT3 reduced mutp53-driven immune suppression and tumor progression. Mutp53 promotes an immunosuppressive TME and facilitates CRPC progression through the STAT3 pathway, underscoring its potential as a therapeutic target.