Disrupting adenosine triphosphate metabolism as a therapeutic strategy against lymphatic cancer progression: a review

Adenosine triphosphate (ATP), the universal cellular energy currency, functions as a central regulator of cancer progression beyond its classical bioenergetic role. This review integrates current evidence on how dysregulated ATP metabolism and signaling contribute to lymphatic cancer progression. Cancer cells undergo metabolic reprogramming, including enhanced glycolysis, fatty acid oxidation (FAO), and oxidative phosphorylation, to sustain elevated ATP production required for proliferation, invasion, and metastasis. ATP plays a pivotal role in lymph node metastasis (LNM), where tumor-derived factors reprogram lymphatic endothelial cells to increase FAO-dependent ATP generation, thereby promoting lymphangiogenesis. Extracellular ATP (eATP) further contributes to tumor progression by activating purinergic receptors, which enhance cancer cell migration and invasiveness. Within the tumor microenvironment (TME), eATP exhibits a dual role. As a damage-associated molecular pattern released during immunogenic cell death, it can stimulate anti-tumor immune responses through dendritic cell activation. However, its rapid hydrolysis by ectonucleotidases CD39 and CD73 produces adenosine, leading to immunosuppression, T-cell exhaustion, and the establishment of an immune-evasive niche, particularly in tumor-draining lymph nodes. ATP-dependent mechanisms also underlie chemoresistance, primarily via ATP-binding cassette (ABC) transporters that actively efflux chemotherapeutic agents. Additionally, the overexpression of ATP-related metabolic enzymes and transporters, including ATP synthase and ATP-citrate lyase (ACLY), correlates with advanced disease stage, metastasis, and poor prognosis. Collectively, ATP-driven pathways represent a critical nexus linking metastasis, immune modulation, and therapeutic resistance, offering promising avenues for biomarker development and targeted therapeutic strategies.