This study explores the development and efficacy of bispecific BCMA/CD24 CAR-T cells in treating multiple myeloma (MM). BCMA-specific CAR-T cells have shown high response rates in MM, but durable remissions are rare due to the persistence of minimal residual MM cells. These residual cells exhibit stem-like features and express CD24, a marker associated with drug resistance and self-renewal. CD24-CAR-T cells were developed to target these residual cells and block the CD24-Siglec-10 pathway, which inhibits macrophage phagocytic clearance of MM cells. The study demonstrates that CD24-CAR-T cells enhance macrophage activity, promoting tumor cell clearance. Additionally, CD24-CAR-T cells polarize macrophages to an M1-like phenotype, which is more effective in tumor clearance. A dual-targeted BCMA/CD24 CAR-T cell showed improved efficacy compared to monospecific BCMA-CAR-T cells. In mouse models, CD24-CAR-T cells significantly reduced tumor burden and improved survival. The study also shows that CD24-CAR-T cells inhibit the CD24-Siglec-10 pathway, leading to activation of inflammatory and antitumor signaling. Furthermore, CD24-CAR-T cells modulate the tumor microenvironment by reducing M2-like macrophages and increasing M1-like macrophages. Bispecific BCMA/CD24 CAR-T cells were also developed, showing enhanced cytolytic activity and improved survival in MM-bearing mice. The study highlights the potential of CD24-CAR-T cells as a promising immunotherapy for MM, targeting both bulk tumor cells and residual disease. The findings suggest that targeting CD24 in combination with BCMA could improve outcomes for MM patients.This study explores the development and efficacy of bispecific BCMA/CD24 CAR-T cells in treating multiple myeloma (MM). BCMA-specific CAR-T cells have shown high response rates in MM, but durable remissions are rare due to the persistence of minimal residual MM cells. These residual cells exhibit stem-like features and express CD24, a marker associated with drug resistance and self-renewal. CD24-CAR-T cells were developed to target these residual cells and block the CD24-Siglec-10 pathway, which inhibits macrophage phagocytic clearance of MM cells. The study demonstrates that CD24-CAR-T cells enhance macrophage activity, promoting tumor cell clearance. Additionally, CD24-CAR-T cells polarize macrophages to an M1-like phenotype, which is more effective in tumor clearance. A dual-targeted BCMA/CD24 CAR-T cell showed improved efficacy compared to monospecific BCMA-CAR-T cells. In mouse models, CD24-CAR-T cells significantly reduced tumor burden and improved survival. The study also shows that CD24-CAR-T cells inhibit the CD24-Siglec-10 pathway, leading to activation of inflammatory and antitumor signaling. Furthermore, CD24-CAR-T cells modulate the tumor microenvironment by reducing M2-like macrophages and increasing M1-like macrophages. Bispecific BCMA/CD24 CAR-T cells were also developed, showing enhanced cytolytic activity and improved survival in MM-bearing mice. The study highlights the potential of CD24-CAR-T cells as a promising immunotherapy for MM, targeting both bulk tumor cells and residual disease. The findings suggest that targeting CD24 in combination with BCMA could improve outcomes for MM patients.