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

Abstract

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 “œcold” HCC lesions into “œhot” ones, thereby improving TACE outcomes and disease control.

Keywords

Hepatocellular carcinoma (HCC) / Transarterial chemoembolization (TACE) / Tumor microenvironment (TME) / Lactic acidosis / Alkalization therapies / Lactate acid inhibition / Nanoparticles

Authors’ contributions

Shuyi Hao: conceptualised the review, conducted the literature search and drafted the manuscript. Hong Yao, Haojie Yu, Lijun Wang: contributed to conceptualization and expert insights. Tingdong Yu, Hongping Xia, Yong Zha: supervised, funding, critical revision and provided expert insights. All authors reviewed and approved the final manuscript.

Declaration of competing interest

The authors declare that there is no conflict of interest.

Acknowledgements

This project was funded by Yunnan Province Science and Technology Talents and Platform Plan Project (No. 202305AF150067); The scientific and technological innovation team building program of Yunnan Provincial Education Depart-ment (No. K1322149); Yunnan Province Talent Support Program (No. CZ0096-901264); Noncommunicable Chronic Diseases-National Science and Technology Major Project (No. 2025ZD0551500, 2023ZD0501500), and Start-up fund of Southeast University & the China Hepatitis Prevention and Treatment Foundation Wang Baoen Liver Fibrosis Research Fund (No. 2025055).

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