Engineering PD-L1 targeted liposomal canagliflozin achieves multimodal synergistic cancer therapy

Immunotherapy-involved combination cancer therapy heralds an unstoppable revolution in clinical practice. However, designing a streamlined approach to integrate immunotherapy with other therapies remains a formidable challenge. Canagliflozin, a clinical drug for type II diabetes, has gained growing interest in cancer therapy, albeit its precise mechanism remains largely elusive. Here, we delve into the multifaceted antitumor mechanisms of canagliflozin, including co-suppression of MAPK/ERK and PI3K/AKT signaling pathways, induction of PD-L1 degradation via ubiquitination and sensitization to X-ray irradiation via downregulation of DNA damage repair-related molecules, thereby offering opportunities for synergistic cancer treatment. For this purpose, we designed a universal nanoliposome coated with a PD-L1-targeting peptide to efficiently deliver canagliflozin in vivo. This simple fabricated nanodrug exhibited specific tumor-targeting ability and excellent biosafety. In vivo anti-cancer efficacy evaluation revealed synergistic pathway-targeted therapy from canagliflozin and immunotherapy facilitated by both canagliflozin and peptide. Furthermore, the introduction of radiotherapy further augmented the overall treatment performance. This study will revisit the diverse anti-tumor mechanisms of canagliflozin and its potential in cancer therapy, greatly expanding its clinical indication. In addition, the targeted delivery system of canagliflozin developed in this study will achieve multimodal synergistic cancer therapy, providing solutions to challenges in clinical cancer treatment and beyond.