Targeting lactic acidosis in the tumor microenvironment: Enhancing TACE efficacy in hepatocellular carcinoma

Lactic acidosis is a hallmark of the tumor microenvironment (TME) and a critical impediment to the efficacy of transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC). Incomplete embolization preserves viable tumor cells that amplify hypoxia-driven glycolysis, generating a lactic acid-rich milieu that drives treatment resistance, skews immune populations toward immunosuppressive phenotypes, and impairs cytotoxic T lymphocyte function. In this review, we elucidate the pathways through which lactic acidosis compromises TACE efficacy and propose novel strategies for its mitigation. We examine emerging approaches, including systemic or intra-arterial alkalization, targeted inhibition of lactate production and export, and calcium carbonate nanoparticles, and evaluate their respective merits and limitations. Finally, we propose a combination regimen of calcium carbonate nanoparticles, lactate-targeting agents, and TACE to achieve precise drug delivery, synergistic lactic acid depletion, and enhanced antitumor immunity. These integrated strategies have the potential to convert immunologically "cold" HCC lesions into "hot" ones, thereby improving TACE outcomes and disease control.