Self-activated prodrug nanocomposites reprogramming lactic acid metabolism to initiate acidosis-endoplasmic reticulum stress cascade and potentiate immunogenic cell death for enhanced liver cancer therapy.

Hepatocellular carcinoma (HCC) remains a major global health challenge, with limited therapeutic efficacy and poor prognosis. To address chemoresistance and immunosuppression in HCC, we developed a lactate-modulating multifunctional prodrug nanocomposite (GD-A NPs). This system is self-assembled from a pentavalent arsenate prodrug (AsO₄³⁻), the hydrogen sulfide (H₂S) donor GYY4137, and the lactate export inhibitor diclofenac (DCF), enabling precise responsiveness to the acidic and reductive tumor microenvironment. Endogenous H₂S selectively reduces intracellular As⁵⁺ to highly cytotoxic As³⁺ in the acidic tumor milieu, thereby activating the prodrug while minimizing systemic toxicity. Simultaneously, H₂S enhances tumor glycolysis-derived lactate production, which, in combination with DCF-mediated inhibition of lactate efflux, leads to intracellular acidification and reversal of the immunosuppressive microenvironment. Excessive lactate accumulation disrupts endoplasmic reticulum (ER) homeostasis, where SERCA2 inhibition depletes ER Ca²⁺ stores and triggers GRP78 dissociation. This event activates PERK-mediated eIF2α phosphorylation and the downstream ATF4/CHOP pathway, ultimately inducing immunogenic cell death (ICD) and promoting systemic immune activation. This is evidenced by the release of damage-associated molecular patterns (DAMPs), dendritic cell maturation, and T cell activation. By integrating lactate metabolism regulation, prodrug activation, and immune remodeling, this strategy provides a promising avenue for combined chemo-immunotherapy of HCC.