In recent years, researchers have identified significant potential in harnessing the human immune system to fight cancer (i.e., cancer immunotherapy). Among these approaches, immune checkpoint blockade targeting the programmed death receptor and its ligand (PD-1/PD-L1) has gained widespread adoption. PD-1 functions as a brake on T cells, suppressing their activity when it binds with PD-L1 on tumor cells. This interaction effectively halts T cell-mediated attacks, allowing cancer cells to evade immune destruction. Although this therapy has shown promise, challenges remain: many patients experience poor T cell infiltration into tumors, develop resistance to the drug, or face interference between multiple immune checkpoints, leading to limited clinical benefits. Studies suggest that simultaneously blocking multiple immune checkpoints could improve efficacy. Another critical immune checkpoint is the CD47 protein. Cancer cells exploit CD47 to bind to SIRPα on immune cells, essentially camouflaging themselves as healthy cells to avoid phagocytosis. When both PD-L1 and CD47 checkpoints are active, cancer cells can evade immune surveillance. Thus, dual blockade of these two checkpoints is essential for activating systemic anticancer immunity. While bispecific antibodies targeting both pathways are available, they risk triggering excessive immune responses (e.g., severe side effects such as high fever and organ damage) and face significant technical and cost barriers. This highlights the need for safer, more manufacturable nanoscale therapeutics that precisely target cancer cells while sparing healthy tissues.
To address this challenge, Professor Zhen Liu’s team at Nanjing University has developed a smart dual-targeting nanodrug designed to dismantle cancer cells’ dual immune evasion mechanisms. This bioinspired nanodrug utilizes advanced recognition technology, functioning like two precision-engineered keys that simultaneously bind to PD-L1 on cancer cells and SIRPα on immune cells. By targeting both sites, it prevents PD-L1-mediated T cell suppression and blocks CD47-induced macrophage evasion. This dual action fully activates the immune system: macrophages transform into scavengers that engulf cancer cells, while reawakened T cells act as precision-guided missiles to target and eliminate tumors. This innovation not only opens new avenues for treating solid tumors but also pioneers a multitarget, synergistic immunotherapy paradigm, highlighting the transformative potential of bioengineering in cancer therapy.
Figure 1. Sche matic illustration of bispecific bsMINIB blocking dual immune checkpoints (ICB).
This study, titled Rationally Engineered Bispecific Nanoimmunoblocker Restores Anticancer Immunity via Dual Immune Checkpoint Blockade, was published in ACS Nano. Professor Zhen Liu from the School of Chemistry and Chemical Engineering at Nanjing University is the corresponding author, with Ph.D. candidate Peixin Guan serving as the first author. The research was supported by the National Natural Science Foundation of China (Key Program, 21834003) and the Nanjing University Excellence Program (ZYJH004).
Paper link:
https://pubs.acs.org/doi/full/10.1021/acsnano.4c13463