Emerging Innate Immune Cells in Cancer Immunotherapy: Promises and Challenges

Immune checkpoint inhibitor (ICI)-based therapy has made an unprecedented impact on survival benefit for a subset of cancer patients; however, only a subset of cancer patients is benefiting from ICI therapy if all cancer types are considered. With the advanced understanding of interactions of immune effector cell types and tumors, cell-based therapies are emerging as alternatives to patients who could not benefit from ICI therapy. Pioneering work of chimeric antigen receptor T (CAR-T) therapy for hematological malignancies has brought encouragement to a broad range of development for cellular-based cancer immunotherapy, both innate immune cell-based therapies and T-cell-based therapies. Innate immune cells are important cell types due to their rapid response, versatile function, superior safety profiles being demonstrated in early clinical development, and being able to utilize multiple allogeneic cell sources. Efforts on engineering innate immune cells and exploring their therapeutic potential are rapidly emerging. Some of the therapies, such as CD19 CAR natural killer (CAR-NK) cell-based therapy, have demonstrated comparable early efficacy with CD19 CAR-T cells. These studies underscore the significance of developing innate immune cells for cancer therapy. In this review, we focus on the current development of emerging NK cells, γδ T cells, and macrophages. We also present our views on potential challenges and perspectives to overcome these challenges.