Purine nucleoside phosphorylase in breast cancer from metabolic regulation to targeted therapy: challenges and opportunities.

Purine nucleoside phosphorylase (PNP) is a key enzyme in the purine salvage pathway that has recently emerged as a potential therapeutic target in cancer. While its role in hematological malignancies is relatively well established, its contribution to solid tumors, particularly breast cancer, remains insufficiently defined. This review aims to critically evaluate the role of PNP in breast cancer progression, with a focus on its involvement in metabolic reprogramming, tumor aggressiveness, and immune modulation, in addition to therapeutic targeting potential. Current evidence indicates that PNP overexpression supports nucleotide homeostasis, promotes proliferation, and contributes to metastatic phenotypes through metabolites such as hypoxanthine. Structural and computational studies have facilitated the development of diverse PNP inhibitors; however, their clinical translation into breast cancer therapy remains limited. A major research gap lies in the lack of mechanistic integration between PNP-driven metabolism, tumor-immune interactions, and subtype-specific breast cancer biology, as well as insufficient in vivo and clinical validation of candidate inhibitors in solid tumors. To address these limitations, future research should focus on integrating multi-omics approaches, advanced computational modeling, and patient-derived models to elucidate PNP-centered metabolic-immune networks. In parallel, the rational design of selective inhibitors with improved pharmacokinetic profiles, combined with biomarker-driven patient stratification and combination therapy strategies, establishes a strong rationale for the development of clinically effective PNP-targeted therapies for breast cancer.