Innate immunity in tumors: From mechanisms to therapeutics

Abstract

Cancer immunotherapy has made significant strides, yet current approaches mainly targeting the adaptive immune system yield limited clinical success. Innate immunity, as the first line of defense, directly eliminates tumor cells and activates adaptive responses. Emerging therapies focused on innate immunity offer a promising frontier to address these challenges. This review explores the functions of major innate immune cells, including natural killer (NK) cells, dendritic cells (DCs), monocytes, macrophages, neutrophils, myeloid-derived suppressor cells (MDSCs), and γδ T-cells within the tumor microenvironment (TME), where they demonstrate both antitumor activity and protumorigenic plasticity. We examine how the TME impairs innate immunity through multiple mechanisms, including dysregulation of immune checkpoints, metabolic reprogramming, inhibitory cytokine signaling, extracellular vesicles, alterations in the extracellular matrix (ECM), and angiogenesis. To overcome these suppressive influences, we highlight emerging therapeutic strategies, including engineered cellular therapies such as chimeric antigen receptor (CAR)-NK cells, CAR-macrophages, and CAR-γδ T-cells to enhance tumor targeting and persistence, and macromolecular strategies (e.g., antibodies, engineered cytokines) to reverse immunosuppression and reprogram the TME. Enhancing innate immunity is key to transforming “cold” tumors into immunologically “hot” ones. Future progress will rely on integrating single-cell multiomics to explore immune heterogeneity, optimizing engineered therapies, and developing combination treatments that leverage both innate and adaptive immunity for more effective cancer immunotherapy.