R. Li1, and X. Peng2; 1West China Hospital, Chengdu, China, 2Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
Purpose/Objective(s): Radiotherapy (RT), a common approach in cancer treatment, encounters challenges arising from RT resistance. In this study, we introduced a dual-responsive intelligent nanosystem named IMM and investigated its ability to reverse RT resistance and regulate the tumor microenvironment. Materials/
Methods: Firstly, in vitro experiments, utilizing Apoptosis assays, Colony formation assay, and Cell migration assays, validated the impact of IMM-augmented RT on apoptosis, proliferation, and migration of cancer cells under hypomoxic conditions. Secondly, the primary mechanism of IMMs sensitization of RT was affirmed through the detection of ROS and HIF1-a expression. Furthermore, the assessment of damage-associated molecular patterns (DAMPs) like ATP, CRT, and HMGB1 provided evidence suggesting potential interactions between IMM-augmented RT and the immune system. The anti-tumor efficacy of IMM-augmented RT was investigated in a colorectal adenocarcinoma mouse model of CT26 tumor-bearing BABL/c mice, and the immunomodulatory effects and vascular normalization mediated by IMM-augmented RT were confirmed. Transcriptomic analysis provided additional insights into the potential molecular mechanism underlying the association between IMM-augmented RT and local tumor growth. Utilizing a mouse model bearing bilateral CT26 tumors, we explored the abscopal effect of combining IMM-augmented RT with PD-1 blockade, while also confirming immunological memory through tumor rechallenge. Results: IMM interacted with endogenous H2O2 under acidic conditions, efficiently generating oxygen and reactive oxygen species (ROS). The ROS exerted direct cytotoxic effects on tumor cells, while oxygen alleviated tissue hypoxia, thereby enhancing the effectiveness of RT, promoting apoptosis of cancer cells and inhibiting their long-term proliferation and migration. IMM-augmented RT inhibited CT26 tumors progression, ameliorated tissue hypoxia, facilitated tumor vessel normalization, and activated the tumor immune microenvironment. When combined with PD-1 blockade, it fully activated the immune system, enhancing abscopal effect, and assisting in the development of long-term immune memory against tumors recurrence and spread. Conclusion: IMM was a dual-responsive intelligent nanosystem, which targeted the high levels of H2O2 and low pH in the tumor hypoxic microenvironment. IMM efficiently produced ROS and oxygen, which directly or indirectly induced tumor cell death, thus achieving radiosensitization. IMM-augmented RT promoted tumor vessel normalization, activated the immune system, and synergistically enhanced the anti-tumor immune effect with PD-1 blockade.
