Lactate-lactylation in tumor angiogenesis and progression: mechanisms, biomarker potential, and therapeutic implications.

Tumor growth and metastasis are critically dependent on the tumor vasculature, which provides essential nutrients and oxygen. Metabolic reprogramming—a hallmark of cancer—drives aggressive progression in solid tumors and is characterized by excessive lactate production. Beyond its role as a glycolytic byproduct, lactate functions as a versatile metabolic substrate and signaling molecule that orchestrates tumor angiogenesis and sustains the immunosuppressive vascular niche. The recent discovery of lysine lactylation has unveiled an epigenetic mechanism through which lactate directly regulates gene expression, thereby bridging metabolic activity with pro-tumorigenic transcriptional programs. Targeting key nodes in lactate metabolism—including biosynthetic enzymes, membrane transporters, and lactylation-modifying machinery—holds substantial promise for biomarker development and therapeutic intervention. Notably, conventional anti-angiogenic therapies often face limitations such as transient efficacy, adaptive resistance, and exacerbation of immunosuppression. In contrast, disrupting lactate production, transport, and lactylation offers a multimodal strategy to reprogram tumor metabolism, normalize aberrant vasculature, and reactivate antitumor immunity. Therefore, We propose that concurrently targeting lactate production, transport, and lactylation constitutes a multimodal therapeutic strategy. By reprogramming tumor metabolism, normalizing the vasculature, and reinvigorating antitumor immunity, this integrated approach may surmount the limitations of current anti-angiogenic therapies and yield more durable clinical outcomes.