Abstract

To address the core issue of low clinical response rates (10%-30%) to α-PD-L1 immune checkpoint blockade therapy, this study targeted the immunosuppressive bottleneck mediated by lactate accumulation in the tumor microenvironment (TME). A targeted drug delivery system (HLC) was constructed using hyaluronic acid (HA) nanomicelles co-loaded with lactate oxidase (LOX) and copper-doped carbon dots (CuCDs). Combined with α-PD-L1, a synergistic antitumor strategy integrating lactate metabolic regulation, cuproptosis, and immune activation was established. HLC achieves targeted accumulation through specific binding between HA and CD44 receptors on tumor cells. It directionally releases LOX and CuCDs in the acidic TME via pH-responsive properties. LOX efficiently clears lactate and elevates pH, blocking the HIF-1α/PD-L1 pathway to reverse immunosuppression. It also generates H 2 O 2 in situ to provide substrates for Cu-mediated Fenton-like reactions, enhancing cuproptosis. In vitro experiments confirm that HLC promotes dendritic cell maturation and drives M2-type macrophage polarization toward the M1 phenotype. In vivo studies using CT26 tumor-bearing mouse models show that HLC combined with 808 nm laser and α-PD-L1 significantly inhibits primary and distant tumor growth. It remodels the antitumor immune microenvironment with favorable biosafety. This study elucidates the synergistic mechanism between lactate metabolic regulation and cuproptosis, establishes an association between lactate level and cuproptosis sensitivity, and provides a novel strategy and experimental basis for combined cancer immunotherapy with important clinical translation value.