Killing three birds with one stone: Multi-stage metabolic regulation mediated by clinically usable berberine liposome to overcome photodynamic immunotherapy resistance

• Limited oxygen perfusion impaired the efficacy of photodynamic therapy. • PD-L1 and IDO1 expression was obviously enhanced after photodynamic therapy. • Tumor-targeting Berberine liposome induced multi-stage metabolic regulation. • Berberine liposome reversed tumor hypoxia, depressed PD-L1 and IDO1 expression. • • Clinically usable Berberine liposome overcome photodynamic immunotherapy resistance. Nowadays, photodynamic therapy (PDT) has become a novel effect modality for cancer therapy. But, facing the extremely hypoxic tumor microenvironment, the efficacy of PDT is still impaired owing to the limited reactive oxygen species (ROS) production. Moreover, after PDT, the overexpression of programmed cell death-ligand 1 (PD-L1) and indoleamine-2,3-dioxygenase-1 (IDO1) could trigger the following impaired T cell infiltration and the further lowered anti-tumor immunity mediated by T cells. Regrettably, up to now, no simple nanosystem could solve these defects of PDT simultaneously and economically. To ameliorate such a situation, we rationally designed and prepared clinically usable hypoxia reversing berberine liposome (BBR@IR68-Lip) with PD-L1 and IDO1 dual-depression capacity simultaneously to overcome photodynamic immunotherapy resistance. In this nanosystem, BBR@IR68-Lip was constructed by using near-infrared photodynamic dye IR68 chemically modified DSPE-PEG 2000 with tumor-targeting capacity as liposome component to encapsulate berberine (BBR) as a novel tumor oxygen and immune microenvironment regulation drug. Owing to the tumor-targeting capacity of IR68-Lip, the accumulation of BBR in tumors further reversed tumor hypoxia, depressed PD-L1 expression, and lowered IDO1 expression via metabolic regulation, which then lead to enhanced ROS generation and amplified T cell infiltration in CT26 tumors. To sum up, in this study, we presented a simple, safe, and clinically usable nanoplatform with ideal tumor re-oxygenation, PD-L1, and IDO1 immune pathways dual-regulation capacity to overcome photodynamic immunotherapy resistance, which may be potential for clinical cancer immunotherapy shortly.