CD47/SIRPα Immune Checkpoint Modulation: A Synergistic Strategy for Next-Generation CAR Therapies

Cancer immunotherapy has been revolutionized through the implementation of the state-of-the-art chimeric antigen receptor (CAR)-mediated therapies. CAR-based technologies, which encompass CAR T cells, CAR macrophages, and CAR NK cells, have shown great promise in the treatment of various cancers. Despite the success of CAR-based therapies in treating malignancies, they face numerous challenges, including dysfunction of effector innate and adaptive immune cells, immunosuppressive tumor microenvironment, antigen heterogeneity, and on-target/off-tumor bio-toxicity. The CD47/SIRPα axis is recognized as a critical innate immune checkpoint and is important in regulating myeloid-derived clearance of tumor cells and the cross-talk between innate and adaptive immune cells in cancer immunity. This signaling axis has risen as a promising target to enhance the CAR-based immunotherapies by overcoming phagocytic inhibition and modulating immune evasion. This narrative review explores the integration of CD47/SIRPα modulation as an adjunct to CAR therapies. CD47/SIRPα immune modulation revealed its potential to boost infiltration, persistence, and phagocytic activity of the immune cells. However, its blockade also poses challenges, including hematologic toxicities, CAR T-cell clearance, and compensatory escape pathways. Future work will depend on selective targeting, combinatorial checkpoint modulation, and engineered CAR designs that preserve safety while unlocking durable responses. Herein, we discuss preclinical and clinical advancements, safety considerations, and cutting-edge advancements.