Researchers develop proximity labeling based antigen amplification technology

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 too sparse on cancer-cell surfaces to effectively activate T cells. Furthermore, these antigens are often present at low levels in normal tissues, leading to poor treatment specificity and potential off-target toxicity.

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 addressed this problem by developing a novel cell-surface protein engineering strategy called Proximity Amplification and Tagging of Cytotoxic Haptens (PATCH), which applies proximity labeling to immunomodulation for the first time.

Proximity labeling, a technique typically used for detecting the spatial relationships among proteins, is an innovative approach originating from chemical biology. In this study, the researchers reimagined proximity labeling as a functional modulation tool. Their goal was to directly amplify targeting signals on the tumor cell surface, thereby identifying the cells that need to be attacked by the immune system.

In the newly developed PATCH strategy, an engineered nanozyme (PCN) was first delivered to the surface of tumor cells and then precisely, noninvasively, and 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 "planted" a high-density cluster of artificial antigens on the target cell’s surface.

Constructed in situ, these high-density antigen clusters subsequently became a "super-beacon" for immune cells. In combination with a bispecific T-cell engager (BiTE) that can simultaneously bind to FITC and the CD3 molecule on the surface of T cells, these clusters efficiently recruited and aggregated T-cell receptors (TCRs), thereby powerfully activating the T cells and 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 clinically derived tumor samples. Specifically, it was shown to completely eliminate the treated tumors and trigger a systemic immune response. The highly efficient tumor-killing process involves the release of a large number of tumor antigens, which in turn stimulate the body's immune system to attack distant, untreated tumors (via an "abscopal effect") and establish long-term immunological memory, effectively preventing tumor recurrence.

This study is the first to expand 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. In addition, it provides a new paradigm for developing precise, efficient, and low-toxicity next-generation immunotherapies.