PTTG1-mediated reprogramming of asparagine metabolism enhances DNA damage repair and leads to compromised antitumor immunity in prostate cancer.

[BACKGROUND] CD8T cell dysfunction is a key factor in immune escape of prostate cancer (PCa). While pituitary tumor-transforming gene 1 (PTTG1) exhibits oncogenic effects in multiple cancers, its role in PCa immunoregulation remains unclear.

[METHODS] Bioinformatics analysis of TCGA data evaluated PTTG1 expression, prognosis, and CD8T cell infiltration. qRT-PCR and western blot (WB) assessed PTTG1 levels in PCa cells. CD8T cell cytotoxicity was measured via LDH release and ELISA (GZMB/TNF-α/IFN-γ). DNA damage was quantified by comet assay and γ-H2AX immunofluorescence. The metabolism of asparagine (Asn) was evaluated by detecting the content of Asn through a kit and the expression of asparagine synthase (ASNS) through WB. A mouse model of allograft tumor was constructed, and the mechanism was verified by immunohistochemistry (PTTG1, ASNS, γ-H2AX, KI67) and flow cytometry detection (proportion of CD8T cells).

[RESULTS] Bioinformatics analysis revealed that PTTG1 was highly expressed in PCa, positively correlated with the poor prognosis of patients, and negatively correlated with CD8T cell infiltration. Cell experiments further demonstrated that PTTG1 inhibited the killing effect of CD8T cells on PCa cells. In addition, in vitro and in vivo experiments showed that PTTG1 promoted DNA damage repair (DDR) of PCa by reprogramming Asn, and targeting PTTG1 enhanced the anti-tumor activity of CD8T cells.

[CONCLUSION] PTTG1 promotes DDR by reprogramming Asn metabolism, thereby inhibiting the function of CD8T cells. Targeting PTTG1 can reverse this process, providing a new strategy for PCa immunotherapy.