Artificial intelligence based miniprotein design to target immunosuppression in cancer

In many cancer types, tumor progression is supported by a local immunosuppressive microenvironment, which limits the immune system’s ability to detect and eliminate malignant cells. One of the key regulators of immune cell signaling is intracellular calcium (Ca²⁺), which controls a wide range of functions including T cell activation, cytotoxicity, and cytokine production. The modulation of calcium dynamics has therefore emerged as a promising strategy for overcoming tumor-associated immune evasion.

Recent evidence indicates that the plasma membrane Ca²⁺ ATPase (PMCA)—a major calcium efflux pump—is functionally enhanced through its interaction with the immune checkpoint receptor LILRB4 (leukocyte immunoglobulin-like receptor B4). This interaction contributes to the suppression of Ca²⁺-dependent immune signaling. By interfering with this pathway, it may be possible to restore immune responsiveness in tumors such as colorectal cancer, which remains one of the leading causes of cancer-related death worldwide.

This research project aims to explore this novel regulatory mechanism and to design AI-driven therapeutic tools that can precisely target LILRB4. Using structural bioinformatics and advanced molecular modeling, we seek to develop nanobody-like proteins (NLPs) and identify small molecule compounds that selectively bind to LILRB4 in specific conformations, disrupting its suppressive signaling and interaction with PMCA.

To validate these new tools, we will apply a combination of in silico design, molecular and cellular assays, and human tumor-derived organoid models, which preserve the complex architecture and immune landscape of colorectal tumors. Our ultimate goal is to establish a proof-of-concept for conformation-specific targeting of immune checkpoint proteins—opening the way for more selective, effective and personalized immunotherapies.

The project is implemented by Semmelweis University in collaboration with the University of Verona and McGill University.