Harnessing innate lymphoid cells (ILCs) for cancer immunotherapy: A new frontier in precision immuno-oncology

Innate lymphoid cells (ILCs) have emerged as critical regulators of tissue immunity, yet their roles in cancer have long been viewed as secondary to adaptive immune responses. Recent advances have fundamentally reshaped this perspective, revealing ILCs as upstream integrators of tumor microenvironmental cues that dynamically shape anti- or pro-tumor immunity. Beyond their canonical subset classification, ILCs exhibit pronounced functional plasticity, adopting context-specific states in response to cytokine, metabolic, neural, and microbial signals within the tumor microenvironment. In this review, we synthesize current insights into the developmental programs, plasticity, and functional heterogeneity of ILCs in cancer, with an emphasis on mechanistic pathways that govern their tumor-modulating activities. We highlight how group 1 ILCs undergo exhaustion and phenotypic reprogramming, how ILC2s can acquire cytotoxic or immunosuppressive properties, and how ILC3 and lymphoid tissue inducer-like cells act as innate architects of tertiary lymphoid structures, thereby shaping local adaptive immune responses and immunotherapy outcomes. Integrating evidence from single-cell and spatial atlases, we discuss how atlas-defined ILC states, rather than fixed subsets, underpin tumor-specific immune landscapes and therapeutic responsiveness. We further examine emerging layers of regulation, including neuro-immune crosstalk and stromal interactions, that refine ILC function within distinct tumor niches. Finally, we explore how atlas-informed targeting of beneficial ILC states, alone or in combination with existing immunotherapies, may enable more precise and effective cancer treatment strategies. Collectively, this review positions ILCs as central orchestrators of tumor immunity and underscores their potential as targets and biomarkers in precision immuno-oncology.