Lactate-Weaponized Microspheres Amplify IL-2–Driven Immuno-Embolization for Hepatocellular Carcinoma

The acidic and immunosuppressive tumor microenvironment (TME) remarkably hampers the therapeutic efficacy of transcatheter arterial embolization (TAE) for hepatocellular carcinoma (HCC). Herein, uniform CaCO 3 nanoparticles encapsulated nickel–alginate microspheres (CaNPs/Ni-Alg MSs) were engineered using a microfluidic device, serving as an immune-regulated embolic agent to amplify TAE treatment of HCC. CaNPs/Ni-Alg MSs could adsorb His-tagged interleukin-2 (IL-2) and enable sustained release through coordination interactions between the His-tag and Ni 2 + , thereby reducing systemic cytokine elevation risk from IL-2 administration. IL-2-loaded microspheres (IL-2/CaNPs/Ni-Alg MSs) effectively neutralize intratumoral lactic acid (LA) via CaCO 3 , modulating the acidic TME. Proton neutralization restores IL-2 activity, enhancing T lymphocyte infiltration and proliferation. Additionally, lactate made available following acid neutralization may serve as a metabolic substrate, as supported by the calcium lactate and neutralization-mimicking experiments in vitro, contributing to CD8 + T-cell metabolic fitness. IL-2/CaNPs/Ni-Alg MSs could reprogram the TME into an immune-promoting milieu, synergizing with immune checkpoint blockade (ICB) therapy to suppress both primary and distant tumors. Not surprisingly, TAE with IL-2/CaNPs/Ni-Alg MSs combined with αPD-L1 achieved superior therapeutic efficacy without side effect in a rat orthotopic HCC model. Overall, this work presents a safe metabolism-reprogramming embolic strategy that repurposes LA to boost IL-2–mediated embolization-immunotherapy in HCC.