Tumor immunotherapies, especially those that leverage T-cells to identify and eliminate cancer cells, represent a major breakthrough in cancer treatment.
However, their widespread application faces two significant hurdles: many tumor-associated antigens are not expressed at a high enough density on the cancer cell surface to effectively activate T-cells; furthermore, these antigens are also often present at low levels in normal tissues, leading to poor treatment specificity and potential off-target toxic side effects. Therefore, developing new strategies that can enhance antigen signals while precisely targeting tumor cells is of paramount importance.
In a study published in Nature, the 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 solved the critical bottlenecks in immunotherapy: insufficient antigen density and poor specificity.
To address this core problem, the research team took an innovative approach from the perspective of chemical biology. They reimagined "proximity labeling"—a technique typically used for "detecting" the spatial relationships of proteins—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 this study, the researchers applied proximity labeling to immunomodulation for the first time, developing a novel cell-surface protein engineering strategy named PATCH (Proximity Amplification and Tagging of Cytotoxic Haptens).
The core of the PATCH strategy is an engineered nanozyme (PCN) that can be activated by red light or ultrasound. The nanozyme is first delivered to the surface of tumor cells, after which external red light or ultrasound provides precise, non-invasive local activation. The activated nanozyme rapidly catalyzes 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 is like "planting" a high-density cluster of artificial antigens on the target cell's surface.
These in-situ constructed, high-density antigen clusters become 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 can efficiently recruit and aggregate T-cell receptors (TCRs). This powerfully activates the T-cells, dramatically enhancing their ability to recognize and kill tumor cells.
The PATCH strategy has achieved breakthrough therapeutic effects in various solid tumor animal models and clinical-derived tumor samples. The research demonstrated that PATCH therapy not only completely eliminated the treated tumors but also, more importantly, triggered 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 research is the first to expand the application of proximity labeling from a "detection tool" for molecular interactions into a powerful "functional modulation tool". Its key advantage lies in solving the problem of insufficient natural antigen density through a catalytic amplification reaction, while ensuring high treatment specificity through precise physical control (light or ultrasound), significantly broadening the range of potential targets for tumor immunotherapy. This work provides a new paradigm and platform for developing precise, efficient, and low-toxicity next-generation immunotherapies.
Reference: https://www.nature.com/articles/s41586-025-09518-6
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