Metal-Phenolic Nanomedicines Regulate T-Cell Antitumor Function for Sono-Metabolic Cancer Therapy

Cancer cells outcompete tumor-infiltrating T lymphocytes(TILs)for glucose uptake, manipulating a glucose-deprived tumor microenvironment(TME) with high accumulation of lactate, which impairs CD8(+) TIL effector function, however supports the immune suppression ofregulatory T (T-reg) cells. Aerobic glycolysis inhibitioncoupled with mitochondrial dysfunction in cancer cells may reprogramTME to destabilize T-reg cells and, more importantly, facilitateCD8(+) T cell activation and cytotoxic killing. Here, a sono-metaboliccancer therapy via hyaluronic acid (HA)-modified metal-phenolic nanomedicine(HPP-Ca@GSK) is proposed to accomplish the aforementioned goals. Abrogatinglactate dehydrogenase A (LDHA) by delivering GSK2837808A (GSK, LDHAinhibitor) successfully suppresses aerobic glycolysis in cancer cellsand creates high-glucose, low-lactate conditions, satisfying the glucosenutrition required by CD8(+) TILs but destabilizing T-reg cells. Meanwhile, depending on ultrasound-mediated oxidativestress, more than 3-fold of calcium (from HPP-Ca@GSK) is mitochondrion-overloaded,amplifying mitochondrial dysfunction and promoting the cancer cellularrelease of damage-associated molecular patterns for more CD8(+) T cell activation and tumor infiltration. In vitro and in vivo studies demonstrate that HPP-Ca@GSK-basedsono-metabolic treatment exhibits impressive anticancer activity.Cooperating with anticytotoxic T lymphocyte-associated protein-4 antibodiesfor enhanced T-reg cell destabilization further improvestherapeutic efficacy. These findings provide a metabolic interventionstrategy for cancer immunotherapy.

Automated summary

Cancer cells compete with tumor-infiltrating T lymphocytes (TILs) for glucose uptake, which alters the tumor microenvironment (TME) and impairs CD8(+) TIL effector function. Inhibiting aerobic glycolysis in cancer cells and inducing mitochondrial dysfunction can reprogram TME and enhance CD8(+) T cell activation. A sono-metabolic cancer therapy using Hyaluronic Acid (HA)-modified metal-phenolic nanomedicine (HPP-Ca@GSK) is proposed to achieve these goals. In vitro and in vivo studies show that HPP-Ca@GSK-based sono-metabolic treatment exhibits significant anticancer activity and can be further enhanced by destabilizing T-reg cells with anticytotoxic T lymphocyte-associated protein-4 antibodies. These findings provide a metabolic intervention strategy for cancer immunotherapy.