Tumor immunotherapies, especially those leveraging T-cells to identify and eliminate cancer cells, represent a major breakthrough in cancer treatment. However, many tumor-associated antigens are not expressed at a high enough density on the cancer cell surface to effectively activate T-cells, and these antigens are often present at low levels in normal tissues, leading to poor treatment specificity and potential off-target toxic side effects.
In a study published in Nature, a research team led by Prof. HAN Shuo from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences applied proximity labeling to immunomodulation for the first time and developed a novel cell-surface protein engineering strategy named Proximity Amplification and Tagging of Cytotoxic Haptens (PATCH), solving the key bottlenecks in immunotherapy.
Proximity labeling, a technique typically used for "detecting" the spatial relationships of proteins, is an innovative approach from the perspective of chemical biology. Researchers reimagined proximity labeling as a functional modulation tool. Their goal was to directly "amplify" targeting signals on the tumor cell surface, thereby "marking" the cells that need to be attacked by the immune system.
In newly developed PATCH strategy, an engineered nanozyme (PCN) was first delivered to the surface of tumor cells, and then precisely, non-invasively, locally activated by external red light or ultrasound. The activated nanozyme rapidly catalyzed the covalent bonding of a large number of probe molecules containing an artificial antigen (FITC) to cell-surface proteins within a few nanometers. This process was like "planting" a high-density cluster of artificial antigens on the target cell's surface.
These in-situ constructed, high-density antigen clusters became a "super-beacon" for immune cells. Using a bispecific T-cell engager (BiTE) that can simultaneously bind to FITC and the CD3 molecule on the surface of T-cells, these clusters could efficiently recruit and aggregate T-cell receptors (TCRs), which powerfully activated the T-cells, dramatically enhancing their ability to recognize and kill tumor cells.
The PATCH strategy has achieved good therapeutic effects in various solid tumor animal models and clinical-derived tumor samples. It can completely eliminate the treated tumors and trigger a systemic immune response. The highly efficient tumor-killing process releases a large number of tumor antigens, which in turn stimulates the body's immune system to attack distant, untreated tumors (an "abscopal effect") and establish long-term immunological memory, effectively preventing tumor recurrence
This study for the first time expands the application of proximity labeling from a "detection tool" for molecular interactions to a powerful "functional modulation tool." It solves the problem of insufficient natural antigen density, while ensuring high treatment specificity, significantly broadening the range of potential targets for tumor immunotherapy. Besides, it provides a new paradigm for developing precise, efficient, and low-toxicity next-generation immunotherapies.
