Oncol Ther. 2026 May 22. doi: 10.1007/s40487-026-00444-9. Online ahead of print.
ABSTRACT
INTRODUCTION: Cancer cells rewire their metabolism toward aerobic glycolysis (the Warburg effect), leading to lactate production that supports tumor growth, hypoxia adaptation, and immune evasion. In this context, syrosingopine, originally developed as an antihypertensive drug, has been repurposed as a dual inhibitor of the lactate transporters MCT1 and MCT4. This dual blockade promotes intracellular lactate accumulation, perturbs NAD+ regeneration, and can induce bioenergetic stress, particularly when combined with mitochondrial metabolic inhibitors. Despite encouraging preclinical data, critical gaps remain regarding immunometabolic remodeling and clinical translation. This narrative review summarizes the repositioning of syrosingopine as a metabolic modulator in oncology, emphasizing mechanistic insights, preclinical efficacy, synthetic lethality with metabolic inhibitors, immunometabolic effects, and considerations for clinical development.
METHODS: We conducted a narrative review of English-language publications on syrosingopine from 2016 to 2026, identified through PubMed and Scopus and supplemented by manual reference screening. Eligible studies investigated syrosingopine in the context of cancer biology, tumor metabolism, immunometabolism, therapeutic mechanisms, nanoformulations, or computational repurposing.
RESULTS: Preclinical studies indicate that syrosingopine inhibits lactate efflux, reduces glycolytic flux, and depletes NAD+, thereby sensitizing cancer cells to biguanides such as metformin and to mitochondrial pyruvate carrier inhibitors such as UK-5099 through a synthetic lethality-like mechanism, inducing apoptosis and cell-cycle arrest. Advanced delivery systems enhance intratumoral drug accumulation, amplify metabolic stress, and remodel the immunosuppressive tumor microenvironment. At the same time, emerging data highlight context-dependent toxicities, including potential exacerbation of liver fibrosis and cardiovascular effects, which may constrain the therapeutic window.
CONCLUSION: Syrosingopine exemplifies a preclinical "lactate trap"-based metabolic intervention with the potential to modulate integrated stress responses and immunometabolic pathways in glycolysis-dependent tumors. Its successful clinical repurposing will require biomarker-guided early-phase trials, optimization of nanoformulations and dosing strategies, incorporation of metabolic imaging readouts, and careful safety monitoring to address tissue-specific toxicities and metabolic plasticity. Graphical abstract available for this article.
PMID:42171986 | DOI:10.1007/s40487-026-00444-9