Targeting the CD47–SIRPα phagocytic checkpoint in cancer: Biology, translational opportunities, and next‐generation therapeutic strategies

Abstract

Abstract Immune checkpoint inhibitors have transformed cancer therapy with the programmed cell death protein 1–programmed death‐ligand 1 axis, demonstrating substantial efficacy by targeting adaptive immunity across multiple malignancies. However, the limited clinical responses observed in a considerable proportion of patients highlights the need for more effective engagement of innate immune mechanisms. In this context, the cluster of differentiation 47–signal regulatory protein α (CD47–SIRPα) axis has emerged as a next‐generation immune checkpoint that regulates phagocytosis. CD47 is a ubiquitously expressed transmembrane glycoprotein containing an N‐terminal extracellular immunoglobulin variable‐like domain and is frequently overexpressed in both solid tumors and hematological malignancies. By binding to SIRPα on macrophages, CD47 transmits a canonical “don't eat me” signal that suppresses phagocytosis and enables tumor immune evasion. Beyond this canonical role, CD47 interacts with ligands such as thrombospondin‐1 and integrins to regulate tumor cell migration, metabolic adaptation, and immune balance within the tumor microenvironment. Importantly, CD47 links innate immune clearance with antigen presentation and downstream adaptive immune activation, positioning it as an actionable node for next‐generation therapeutic designs. Although the first‐generation CD47 blockade has revealed challenges related to hematologic toxicity, antigen sink effects, and limited monotherapy durability, these challenges have also accelerated the development of more selective, controllable, and context‐responsive therapeutic strategies. In this Review, we elucidate the structural features, molecular mechanisms, pathological functions, therapeutic strategies, translational challenges, and emerging solutions of CD47, with the aim of providing a theoretical basis for overcoming current therapeutic limitations and advancing more precise cancer immunomodulatory strategies.