Innate immune cells in tumor immunity: dual roles, mechanistic insights, and therapeutic opportunities

Abstract

The tumor microenvironment (TME) is a complex ecosystem that dynamically regulates tumor progression and therapeutic responses. Within this environment, innate immune cells play prominent dual roles, acting as both critical mediators of anti-tumor surveillance and facilitators of tumor immune escape. This review comprehensively synthesizes the phenotypic plasticity and functional heterogeneity of key innate immune cell subsets in tumor immunity, including tumor-associated macrophages (TAMs), natural killer (NK) cells, tumor-associated neutrophils (TANs), dendritic cells (DCs), as well as emerging players such as γδ T cells and innate lymphoid cells (ILCs). Mechanistically, we dissect core pathways governing innate immune cell function in the TME: the cGAS-STING pathway regulates type I interferon responses and immunogenicity; the NF-κB/STAT3 network coordinates inflammation and immunosuppression; the PD-1/PD-L1 axis mediates T cell exhaustion and innate cell dysfunction. Additionally, tumor-driven metabolic reprogramming and extracellular vesicles (EVs) intercellular communication collectively shape the immunosuppressive TME. We further evaluate emerging therapeutic strategies targeting innate immunity. This narrative review provides a comprehensive mechanistic framework and theoretical basis for developing precise, innate immunity-targeted cancer immunotherapies.