Proximity-guided graph learning reveals tumour-associated proximity antigens.

Abstract

The spatial organization of membrane proteins is an underexplored dimension of cell surface biology^1,2. Spatial proximity shapes cellular function and therapeutic targetability^2,3, yet efforts to identify tumour-associated antigens (TAAs) have largely focused on expression alone⁴. Here, we developed an industrialized surface protein proximity-mapping workflow to interrogate TAAs within their membrane microenvironments. Using this workflow, we generated 248 proximity maps across 12 receptor tyrosine kinases and 28 tumour cell systems. The resulting atlas enabled the development of MetaMap, a correlation-based analytical framework that defines spatial protein communities and infers conserved proximity relationships among non-targeted proteins, and establishes the concept of tumour-associated proximity antigens (TAPAs), a class of co-targets defined by disease-specific spatial proximity to TAAs rather than expression alone. Integrating these proximity-derived relationships within a multimodal prioritization framework, we identified and validated EGFR-CDCP1 as a TAA-TAPA pair that enhances tumour cell killing across therapeutic modalities. Together, this work advances disease-associated membrane proximity as a guiding principle for the design of precision multispecific therapeutics.