Light-inducible nanodrug-mediated photodynamic and anti-apoptotic synergy for enhanced immunotherapy in triple-negative breast cancer

• Published in: Biomaterials science 2024-05, Vol.12 (1), p.2639-2647
• Main Authors: Huang, Jing, Liu, Xingliang, Lin, Minzhao, Xiao, Zecong, Shuai, Xintao
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; Cell death; Cell Line, Tumor; Chlorophyllides; Female; Humans; Immune system; Immunotherapy; Infrared lasers; Irradiation; Lymphocytes; Mice; Nanoparticles - chemistry; Nitrophenols - chemistry; Nitrophenols - pharmacology; Photochemotherapy; Photosensitizing Agents - administration & dosage; Photosensitizing Agents - chemistry; Photosensitizing Agents - pharmacology; Piperazines - chemistry; Piperazines - pharmacology; Porphyrins - chemistry; Porphyrins - pharmacology; Reactive Oxygen Species - metabolism; Sulfonamides - chemistry; Sulfonamides - pharmacology; Synergistic effect; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - immunology; Triple Negative Breast Neoplasms - pathology; Triple Negative Breast Neoplasms - therapy
• ISSN: 2047-4830; 2047-4849
• DOI: 10.1039/d4bm00083h

Triple negative breast cancer (TNBC) exhibits limited responsiveness to immunotherapy owing to its immunosuppressive tumor microenvironment (TME). Here, a reactive oxygen species (ROS)-labile nanodrug encapsulating the photosensitizer Ce6 and Bcl-2 inhibitor ABT-737 was developed to provoke a robust immune response via the synergistic effect of photodynamic therapy (PDT) and the reversal of apoptosis resistance. Upon exposure to first-wave near-infrared laser irradiation, the generated ROS triggers PEG cleavage, facilitating the accumulation of the nanodrug at tumor region and endocytosis by tumor cells. Further irradiation leads to the substantial generation of cytotoxic ROS, initiating an immunogenic cell death (ICD) cascade, which prompts the maturation of dendritic cells (DCs) as well as the infiltration of T cells into the tumor site. Meanwhile, Bcl-2 inhibition counteracts apoptosis resistance, thereby amplifying PDT-induced ICD and bolstering antitumor immunity. As a result, the ROS-sensitive nanodrug demonstrates a potent inhibitory effect on tumor growth. An ROS-labile nanodrug co-encapsulating Ce6 and a Bcl-2 inhibitor enabled PDT and reversed apoptotic resistance, demonstrating a potent inhibitory effect on tumor growth.