The versatility of SIRPα: Novel perspectives on tumor microenvironment regulation and targeted therapy beyond the CD47-SIRPα axis.

Signal regulatory protein α (SIRPα), a receptor for CD47, is widely expressed on myeloid cells and certain tumor cells. Its canonical function involves transmitting a "don't-eat-me" signal through the CD47-SIRPα axis, thereby mediating tumor immune escape. Recent studies have revealed that SIRPα has diverse and context-dependent roles in the tumor microenvironment. In tumor cells, its expression may suppress pyroptosis, promote metastasis, or potentially enhance T-cell immune responses. In dendritic cells, macrophages, and neutrophils, SIRPα modulates cell activation, polarization, migration, and phagocytic capacity. These effects collectively influence both innate and adaptive immune responses. Furthermore, various novel therapeutic strategies-including small-molecule inhibitors, bispecific antibodies, nanoparticle-based agents, and combination therapies-are advancing SIRPα-targeted treatment beyond traditional blockade. These advances move toward precise, synergistic immunotherapy with broad clinical potential.