NK cells and innate lymphoid cells in the tumor microenvironment: Cytokine crosstalk, immune checkpoints, and biomarker potential

Natural killer (NK) cells and innate lymphoid cells (ILCs) are critical components of the innate immune system and play diverse roles in tumor surveillance, immune regulation, and tissue homeostasis. Within the tumor microenvironment (TME), their functions are shaped by complex interactions with malignant cells, stromal populations, and other immune cells. Cytokines and chemokines, including IL-12, IL-15, IL-18, TGF-β, and CXCL family members, can profoundly influence NK/ILC activation, differentiation, recruitment, and functional plasticity. At the same time, tumor-associated immune checkpoints and suppressive signals can impair their cytotoxicity and promote dysfunctional or tumor-supportive phenotypes. Increasing evidence suggests that NK cells and ILC subsets may serve as informative biomarkers of tumor progression, treatment response, and patient outcomes. Understanding these interconnected pathways may reveal new mechanisms of immune evasion and identify opportunities for biomarker development and innovative immunotherapeutic strategies.Despite growing recognition of NK cells and ILCs as important regulators of tumor immunity, substantial gaps remain in understanding how their functional states are established and remodeled within the TME. The complex cytokine and chemokine networks, metabolic conditions, cellular interactions, and immune checkpoint signals present in tumors can drive considerable heterogeneity and plasticity among NK and ILC populations, making their biological and clinical significance difficult to define. Recent advances in single-cell and spatial transcriptomics, high-dimensional flow cytometry, multi-omics approaches, and functional profiling have enabled more detailed characterization of NK/ILC subsets and their interactions within tumors. This Research Topic aims to integrate emerging evidence on cytokine-mediated crosstalk, immune checkpoint regulation, cellular plasticity, and tumor–immune interactions involving NK cells and ILCs. Particular emphasis will be placed on identifying robust biomarkers, clarifying mechanisms of immune dysfunction, and exploring strategies to enhance NK/ILC-mediated antitumor responses, including combination immunotherapies and approaches that can overcome TME-mediated suppression.This Research Topic welcomes original and translational research addressing the multifaceted roles of NK cells and innate lymphoid cells (ILCs) within the tumor microenvironment. Contributions may focus on, but are not limited to:• Cytokine and chemokine crosstalk regulating NK/ILC activation, differentiation, recruitment, and plasticity.• NK/ILC interactions with tumor, stromal, myeloid, and adaptive immune cells.• Immune checkpoints and mechanisms underlying NK/ILC dysfunction and immune evasion.• Metabolic, hypoxic, acidic, and nutrient-related factors affecting NK/ILC function.• NK/ILC-derived biomarkers for diagnosis, prognosis, treatment response, and patient stratification.• Novel NK/ILC-based immunotherapies, including CAR-NK and combination therapeutic strategies.• Single-cell, spatial, multi-omics, computational, and systems-immunology approaches to characterize NK/ILC populations.• Clinical and translational studies investigating NK/ILC signatures and their relevance to patient outcomes.We welcome Original Research, Review, Systematic Review, Meta-Analysis, Mini Review, Brief Research Report, Case Report, Clinical Trial, Hypothesis and Theory, Opinion, and General Commentary articles that provide mechanistic, translational, methodological, or clinically relevant insights into NK and ILC biology in cancer.Please note Dr Bin Liu is the co-inventor on pending patents WO2019217898A1, US20220280609A1 and P-660794-USP. Dr Liu also serves on the Board of Directors for Abiocode, Inc., a reagent Biotech company. Topic editors: Noha Mousaad Elemam, Bin Liu Source: https://www.frontiersin.org/research-topics/86782/nk-cells-and-innate-lymphoid-cells-in-the-tumor-microenvironment-cytokine-crosstalk-immune-checkpoints-and-biomarker-potential