Innate Immunity–Stroma Crosstalk in the Tumor Microenvironment: Mechanisms and Therapeutic Opportunities

The tumor microenvironment (TME) is an active ecosystem in which stromal elements—most prominently cancer-associated fibroblasts (CAFs), vasculature, and extracellular matrix—continuously shape innate immune behavior. Within solid tumors, this bidirectional crosstalk often redirects natural killer (NK) cells, macrophages, neutrophils, and dendritic cells away from anti-tumor functions and toward tolerance, thereby blunting immunotherapy. CAFs remodel matrix architecture, secrete immunomodulatory mediators (e.g., TGF-β, IL-6, CXCL12), and rewire nutrient fluxes that constrain innate cell recruitment, activation, and cytotoxicity. NK cells, despite intrinsic tumor surveillance capacity, frequently downregulate activating receptors (e.g., NKG2D, DNAM-1) and exhibit metabolic exhaustion under stromal control, including glucose and arginine deprivation. Similar stromal cues polarize macrophages toward tumor-promoting phenotypes and impede antigen-presenting programs in dendritic cells. Collectively, these circuits create spatial and metabolic barriers, dampen cytolytic signaling, and seed resistance to immune checkpoint and cell-based therapies. Elucidating the cellular, molecular, and biophysical logic of innate immunity–stroma interactions across tumor types will clarify why some lesions remain refractory and reveal exploitable vulnerabilities to restore innate effector function.This Research Topic will illuminate how stromal programs sculpt innate immune responses and, in turn, determine therapeutic outcomes in solid tumors. We welcome studies that resolve the molecular and metabolic wiring of CAF–innate cell communication, define how matrix mechanics and vascular niches regulate trafficking and receptor signaling, and explain mechanisms of resistance to checkpoint blockade and NK- or myeloid-targeted therapies. A central aim is to translate mechanistic insight into actionable strategies—such as stromal pathway inhibition, matrix normalization, metabolic support, and engineered cell therapies—to reinvigorate innate surveillance and synergize with existing immunotherapies. By integrating multi-scale profiling with rigorous experimental validation, we seek to build a roadmap for rationally modulating the stromal milieu to unlock durable clinical responses.● CAF regulation of NK, macrophage, neutrophil, and dendritic cell recruitment, activation, and cytotoxicity in solid tumors● Molecular mediators of crosstalk (e.g., TGF-β, IL-6, CXCL12, MMPs; NKG2D/DNAM-1 ligands; checkpoint ligands)● Metabolic competition and support (glucose, amino acids, lipids) and consequences for innate effector fitness● ECM architecture and mechanics controlling innate immune trafficking and synapse formation● Vascular and hypoxic niches shaping innate cell positioning and function● Strategies to overcome stromal suppression: pathway inhibitors, matrix normalization, metabolic adjuvants, and combination regimens● Preclinical models (3D organoids, ex vivo slices, humanized and syngeneic mouse models) and translational studies targeting the stroma–innate axis● Biomarkers and spatial/multi-omics correlates predicting response to stromal or innate-directed therapiesPlease note: Manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases, which are not accompanied by validation (independent clinical or patient cohort, or biological validation in vitro or in vivo, which are not based on public databases) are not suitable for publication in this journal. Topic editors: Yongbo Zheng, Zequn Li Source: https://www.frontiersin.org/research-topics/75070/innate-immunity-stroma-crosstalk-in-the-tumor-microenvironment-mechanisms-and-therapeutic-opportunities