Photothermal ?nano-dot? reactivate ?immune-hot? for tumor treatment via reprogramming cancer cells metabolism

Cancer immunotherapy, despite its enormous application prospect, is trapped in the abnormal lactic acid metabolism of tumor cells that usually causes an immunosuppressive tumor microenvironment (ITM). Inducing immunogenic cell death (ICD) not only sensitizes cancer cells to carcer immunity, but also leads to a great in-crease in tumor-specific antigens. It improves tumor condition from immune-cold to immune-hot. Herein, a near-infrared photothermal agent NR840 was developed and encapsulated into tumor-targeted polymer DSPE-PEG-cRGD and carried lactate oxidase (LOX) by electrostatic interaction, forming self-assembling nano-dot PLNR840 with high loading capacity for synergistic antitumor photo-immunotherapy. In this strategy, PLNR840 was swallowed by cancer cells, then dye NR840 was excited at 808 nm to generate heat inducing tumor cell necrosis, which further caused ICD. LOX could serve as a catalyst, reducing lactic acid efflux via regulation of cell metabolism. More importantly, the consumption of intratumoral lactic acid could substantially reverse ITM, including promoting the polarization of tumor-associated macrophages from M2 to M1 type, inhibiting the viability of regulatory T cells for sensitizing photothermal therapy (PTT). After the combination of alpha PD-L1 (programmed cell death protein ligand 1), PLNR840 restored CD8+ T-cell activity that thoroughly cleaned the pulmonary metastasis of breast cancer in 4T1 mouse model and cured hepatocellular carcinoma in Hepa1-6 mouse model. This study provided an effective PTT strategy to boost immune-hot and reprogrammed tumor metabolism for antitumor immunotherapy.

Automated summary

Cancer immunotherapy is enhanced by inducing immunogenic cell death (ICD) and regulating tumor metabolism using a self-assembling nano-dot PLNR840, which contains a near-infrared photothermal agent and lactate oxidase (LOX). This strategy effectively improves the immune status and antitumor effect in mouse models of breast cancer and hepatocellular carcinoma.