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Engineering a PD-L1-sensing synthetic receptor for programmable macrophage response
Ilaria De Martino1,2, Luigi Russo3, Matteo Marchetti1,4
1Istituto Italiano di Tecnologia-IIT, Largo Barsanti e Matteucci, 80125, Naples, Italy.
Journal of Biological Engineering
|June 6, 2026
Summary
Scientists engineered a synthetic receptor (SNIPR) to detect programmed death-ligand 1 (PD-L1). This allows engineered cells to activate phagocytosis, enhancing cancer cell engulfment and offering a new way to control immune responses.
Area of Science:
- Synthetic biology
- Immunology
- Cellular engineering
Background:
- Cellular decision-making integrates extracellular cues for functional responses.
- Synthetic biology enables rewiring cellular processes with engineered receptors.
- Programmed death-ligand 1 (PD-L1) is a key immune-regulatory ligand.
Purpose of the Study:
- To engineer a synthetic receptor that enables monocytic-like cells to sense PD-L1.
- To conditionally activate a phagocytic program in response to PD-L1.
- To establish a modular framework for ligand-responsive control of engineered macrophage behavior.
Main Methods:
- Engineered a synthetic Notch-based receptor (SNIPR) to detect PD-L1.
- Programmed SNIPR to trigger outputs like fluorescent reporters or CV1-Fc upon PD-L1 engagement.
- Utilized THP-1-derived macrophages and SKOV-3 ovarian cancer cells for in vitro experiments.
Main Results:
- SNIPR activation scaled with PD-L1 levels.
- The circuit partially attenuated PD-1/PD-L1 signaling.
- Conditional CV1-Fc expression enhanced macrophage engulfment of cancer cells.
Conclusions:
- PD-L1 can be repurposed from a therapeutic target to a programmable input signal for synthetic circuits.
- This work establishes a modular framework for ligand-responsive control of engineered macrophage behavior.
- The engineered system offers a novel approach for modulating immune responses in cellular therapies.
