Natural killer cells, macrophages and dendritic cells as innate immune therapies for blood cancers.

Innate immune cells are emerging as powerful allies in the fight against blood cancers. Natural Killer (NK) cells, macrophages, and dendritic cells (DCs)—once viewed mainly as supporting players—are now at the forefront of next-generation immunotherapies, owing to their rapid, antigen-independent tumor recognition and potent effector functions. This review highlights their distinct anti-tumor roles: NK cells’ cytotoxicity and “missing-self” recognition, the dual and adaptable nature of macrophages in the tumor microenvironment (TME), and the antigen-presenting capabilities of DCs that bridge innate and adaptive immunity. We further examine transformative therapeutic strategies, including adoptive NK cell transfer, CAR-engineered NK cells (CAR-NK), CAR-macrophages (CAR-M), and DC vaccines, with a focus on clinical outcomes and safety—particularly the encouraging toxicity profile of CAR-NK cells. Despite these advances, major challenges persist, including limited persistence and homing of infused cells, TME-driven immunosuppression, and potential on-target/off-tumor effects. To overcome these barriers, synergistic approaches that integrate innate immune therapies with checkpoint inhibitors, conventional treatments, innovative engineering, and precise modulation of the TME will be essential. These strategies hold the promise of translating scientific breakthroughs into durable, safe, and widely accessible treatments for patients with hematological malignancies.