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 CaCO3 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 Ni2 +, 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 CaCO3, 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.