Clinical advances in CD47-SIRPα axis-targeted cancer immunotherapy: Mechanisms, strategies, challenges, and future perspectives.

The CD47-SIRPα signaling axis has emerged as a promising target in cancer immunotherapy by disrupting the "don't eat me" signal, thereby promoting macrophage-mediated phagocytosis. However, its clinical translation confronts a significant challenge due to the "on-target off-tumor" effect, primarily leading to hematological toxicity, notably anemia. This challenge was underscored by a pivotal setback in the field: the Phase III trial of Magrolimab, the first anti-CD47 therapy to reach this stage, which failed to meet its primary endpoint and ultimately led to the discontinuation of its development program. This comprehensive review systematically traces the evolution of therapeutic strategies targeting the CD47-SIRPα axis, from first-generation monoclonal antibodies to advanced fusion proteins, bispecific antibodies, and cutting-edge approaches such as oncolytic viruses and CAR-macrophages. It also provides a detailed summary of the clinical trial landscape, analyzing the differential efficacy observed between hematological malignancies and solid tumors. Furthermore, we summarize the major clinical challenges, including safety concerns, resistance mechanisms, and diagnostic complexities. By synthesizing these key findings, this review provides valuable insights for optimizing future drug design, refining combination regimens, and guiding patient selection strategies, thereby offering a crucial reference for overcoming current limitations and fully realizing the therapeutic potential of this promising axis.