2-deoxy-d-ribose: A multifaceted player at the crossroads of cancer metabolism

Understanding metabolic interactions within the tumor microenvironment (TME) remains a major challenge in cancer research with significant clinical implications. Among the metabolites shaping the TME, 2-deoxy-D-ribose (2dDR) has emerged as a key player. Oncogenic drivers can elevate 2dDR levels by directing carbon flux toward the pentose phosphate pathway (PPP) and nucleotide biosynthesis. This increases substrate availability for nucleoside phosphorylases, particularly thymidine phosphorylase (TP), as the primary enzymatic source of 2dDR. However, the mechanisms uniquely linking TP overexpression to 2dDR accumulation in cancer remain poorly understood. Resolving this gap is critical given 2dDR's roles in promoting angiogenesis, inducing reactive oxygen species and enabling an alternative metabolic route in cancer cells. 2dDR therefore represents a compelling node for therapeutic intervention. This review summarizes current research on biosynthesis, regulation and downstream effects of 2dDR in tumor biology, thereby establishing its role as a metabolic and signaling intermediate in cancer progression.