Engineering nanoliposomes to enhance cancer immunotherapy by reversing immunosuppression and synergistically boosting tumour immunogenicity

The clinical success of immune checkpoint inhibitors (ICIs) has initiated a new era in the treatment of metastatic cancer. Unfortunately, the overall response rate of ICIs in pretreated metastatic breast cancer (BC) is generally less than 20% due to many challenges, including low immunogenicity and immunosuppressive tumour microenvironment (ITM). Herein, we synthesized nanoliposomes that codelivered diclofenac (DC) and Mn (5,10,15,20-tetrakis (4-chlorophenyl) porphyrin) Cl (PMnCl) (denoted MD@Lip) to overcome these challenges. DC could block lactate transporters (monocarboxylate transporters 1 and 4) on the cancer cell membrane, thus reducing the concentration of lactate, which acts as a critical regulator of the ITM. Meanwhile, PMnCl-induced sonodynamic therapy (SDT) could induce apoptotic and/or necrotic tumour cell death. Importantly, SDT could induce immunogenic cell death (ICD) during the tumour cell debris generation, which changed the state of tumour cells from nonimmunogenic to immunogenic. Thus, MD@Lip was verified to activate T cells, inactivate regulatory T cells and regulate the levels of immune cytokines, ultimately inhibiting primary and distant tumours by improving the antitumour effect of anti-PD1-based immunotherapy.