Lactate Oxidase Nanocapsules Boost T Cell Immunity and Efficacy of Cancer Immunotherapy

Cancer immunotherapy has reshaped the landscape of cancer treatment, but its effectiveness in solid tumors is limited by the overproduction of lactate by cancer cells. Extensive trials are being conducted to reduce lactate concentrations through inhibiting lactate dehydrogenase. However, such inhibitors often disrupt the metabolism of healthy cells and cause non-specific toxicity. In contrast to those strategies, we target lactate itself with an enzyme, lactate oxidase, which effectively reduces lactate concentrations and releases hydrogen peroxide, an immunostimulatory molecule, in the tumor microenvironment. However, recombinant lactate oxidase from microorganisms possesses short circulating half-life, low enzyme activity, and potential immunogenicity. To circumvent this limitation, we report herein a nano-encapsulating strategy to encapsulate lactate oxidase molecules within a thin polymer shell through in-situ polymerization, affording the synthesis of nanocapsules. The nanocapsules stabilize lactate oxidase and prevent it from proteolysis and denature, minimize the immunogenicity, prolong the circulating half-life, enabling their use as a potent therapeutic for cancer immunotherapy. Lactate oxidase nanocapsules can promote the proliferation and activation of effector T cells and suppress tumor-resident regulatory T cells <i>in vitro</i>. As further demonstrated in a murine melanoma model and a humanized mouse model of triple-negative breast cancer, nanocapsules avert tumor immunosuppression and enhance anti-tumor T cell immunity by upregulating gene expression for T cell recruitment and activation, as confirmed by single-cell RNA sequencing. Such multifunctional lactate oxidase nanocapsules lead to improved efficacy of immunotherapies for solid tumors.