The acidic tumor microenvironment in hepatocellular carcinoma: a barrier to adoptive cellular immunotherapy

The metabolic interface between tumor and immune cells is an emerging determinant of immunotherapy resistance, yet its therapeutic exploitation in hepatocellular carcinoma (HCC) remains limited. Adoptive cellular immunotherapies, including NK cell infusion, tumor-infiltrating lymphocytes (TILs), and chimeric antigen receptor T (CAR-T) cells, have transformed hematologic oncology but repeatedly fail to achieve durable responses in HCC. We argue that an underappreciated driver of this resistance is the acidic tumor microenvironment (TME): hypoxia-driven glycolytic reprogramming acidifies the HCC niche through lactate and proton accumulation, lowering extracellular pH (pHe) to approximately 6.5-6.8 (measured 6.66 ± 0.19 in human HCC by CEST MRI), rewiring macrophages, neutrophils, dendritic cells, NK cells, myeloid-derived suppressor cells, and T lymphocytes toward immunosuppressive or exhausted states. Although lactate and tumor acidity have each been reviewed extensively, the specific implications of acidosis for the design and delivery of cell-based therapies remain scattered and unsynthesized, a gap of growing urgency as the first pH-targeting and acidity-armored cellular products enter clinical testing, as summarized in this review. This mini review delineates how the acidic TME is established in HCC, summarizes cell-type-specific mechanisms of acidosis-driven immune dysfunction, and critically evaluates unresolved issues: the incomplete dissociation of acidity- versus lactate-mediated effects, the metabolic double-edged sword of systemic glycolytic blockade, and the gap between preclinical pH modulation and clinical translation. We conclude that ex vivo metabolic preconditioning and acidity-responsive cell engineering, rather than systemic metabolic intervention, offer the most tractable path toward durable cellular immunotherapy in HCC.