Cancer-derived lactic acid as a potential upstream contributor to tumor hypoxia

Hypoxia contributes to tumor progression, abnormal blood vessel formation, immune suppression, and therapeutic resistance. Although hypoxia is traditionally viewed as the primary driver of glycolysis, intrinsic oncogenic signaling, mitochondrial dysfunction, and epigenetic reprogramming also stimulate glycolysis independently of oxygen limitation, leading to substantial lactic acid accumulation under oxygenated conditions. Beyond its classic role in metabolism, lactic acid is a bioactive molecule that shapes tumor physiology by influencing immune responses, driving vascular remodeling, and mediating metabolic interactions among tumor and stromal populations. In this Perspective, we propose that cancer-derived lactic acid may contribute to the development and persistence of hypoxic tumor regions and sustain hypoxia-associated signaling. This framework positions lactic acid not only as a consequence of hypoxia but also as a potential upstream driver, forming a self-reinforcing glycolysis-lactic acid-hypoxia feedback loop that can be therapeutically disrupted by targeting lactic acid production or transport.