The NKG-hSIRPα mouse is a humanized model constructed by replacing the exon 2 coding region plus partial intron 2 of the mouse Sirpa gene in situ with the "Human SIRPA CDS-3'UTR of Mouse Sirpa-WPRE-BGH pA" cassette. The homozygous NKG-hSIRPα mice are viable and fertile. Compared with NKG mice, NKG-hSIRPα mice further inhibit the phagocytosis of transplanted tumors by host macrophages through enhancing the function of the CD47-SIRPα signaling pathway, thus accelerating tumor growth. This model provides a crucial experimental platform for studying the ability of CAR-M therapy to overcome the immunosuppressive microenvironment, as well as for developing anti-tumor drugs targeting the CD47/SIRPα pathway.