Cell surface receptors and their interactions play a central role in physiological and pathological signaling. Despite its clinical relevance, the immunoglobulin superfamily (IgSF) remains uncharacterized and underrepresented in databases. Here, we present a systematic extracellular protein map, the IgSF interactome. Using a high-throughput technology to interrogate most single transmembrane receptors for binding to 445 IgSF proteins, we identify over 500 interactions, 82% previously undocumented, and confirm more than 60 receptor-ligand pairs using orthogonal assays. Our study reveals a map of cell-type-specific interactions and the landscape of dysregulated receptor-ligand crosstalk in cancer, including selective loss of function for tumor-associated mutations. Furthermore, investigation of the IgSF interactome in a large cohort of cancer patients identifies interacting protein signatures associated with clinical outcome. The IgSF interactome represents an important resource to fuel biological discoveries and a framework for understanding the functional organization of the surfaceome during homeostasis and disease, ultimately informing therapeutic development.

细胞表面受体及其相互作用在生理和病理信号传导中起着核心作用。尽管具有临床相关性，但免疫球蛋白超家族（IgSF）仍未表征，数据库中的代表性不足。在这里，我们介绍了系统的细胞外蛋白质图谱，即IgSF相互作用组。使用高通量技术来查询大多数单跨膜受体以结合445 IgSF蛋白，我们鉴定了500多种相互作用，其中82％以前未记录，并使用正交试验确定了60多个受体-配体对。我们的研究揭示了癌症中细胞类型特异性相互作用的图谱以及受体-配体串扰失调的情况，包括肿瘤相关突变的选择性功能丧失。此外，在一大批癌症患者中对IgSF相互作用基因组的研究确定了与临床结果相关的相互作用蛋白特征。IgSF相互作用基因组是促进生物学发现的重要资源，也是理解稳态和疾病过程中表面组功能组织的框架，最终为治疗发展提供了信息。