Neuroimmune and metabolic regulation of the tumor microenvironment in immunotherapy

Recent advances in cancer immunology have established the tumor microenvironment (TME) as a dynamic regulator of therapeutic response. Metabolic competition, nutrient depletion, ionic disequilibrium, extracellular acidosis, and spatial heterogeneity can impair T-cell function and promote immune evasion. These processes are further shaped by interactions among tumor cells, immune populations, stromal cells, vasculature, and extracellular matrix components. Emerging evidence also indicates that tumor and infiltrating immune cells can produce and respond to neurotransmitters, including catecholamines, glutamate, GABA, and acetylcholine, revealing an additional layer of neuroimmune regulation. Although single-cell, spatial, and functional technologies have begun to resolve these complex ecosystems, the mechanisms linking metabolic, ionic, spatial, and neurotransmitter networks remain incompletely understood. Defining these interactions will be essential for developing rational strategies to overcome immunotherapy resistance and improve patient benefit.This Research Topic aims to elucidate how interconnected TME networks regulate immune-cell activity, immune evasion, and responsiveness to cancer immunotherapy. Particular emphasis will be placed on the crosstalk between metabolic reprogramming, ionic and pH dysregulation, spatially organized cellular niches, and neurotransmitter-mediated signaling. Recent advances in single-cell sequencing, spatial transcriptomics, spatial proteomics, metabolomics, and functional imaging provide unprecedented opportunities to characterize these processes at cellular and regional resolution. We welcome studies that identify molecular mechanisms underlying TME-driven immunosuppression, define biomarkers of treatment response or resistance, and evaluate therapeutic strategies that selectively remodel the TME. The Research Topic also seeks work that bridges fundamental discovery with translational oncology, including rational combination approaches involving immune checkpoint blockade, cellular therapy, metabolic intervention, neuromodulation, or other TME-directed treatments.This Research Topic will focus on mechanistic and translational studies investigating how interacting metabolic, ionic, spatial, and neuroimmune processes influence immunotherapy responses across solid tumors. Studies should provide clear relevance to antitumor immunity, therapeutic resistance, biomarker development, or clinical translation. We welcome articles addressing, but not limited to, the following themes:• Metabolic reprogramming of tumor and immune cells and its effects on antitumor immunity;Nutrient competition, metabolite signaling, and metabolically compartmentalized TME niches;• Ionic homeostasis, extracellular acidosis, hypoxia, and their effects on T-cell and myeloid-cell function;• Neurotransmitter synthesis, release, and receptor signaling in tumor, immune, and stromal cells;• Neuroimmune–tumor crosstalk involving norepinephrine, dopamine, GABA, glutamate, acetylcholine, or related mediators;• Spatial and spatiotemporal TME heterogeneity revealed by single-cell and spatial multi-omics;• Interactions among metabolic, ionic, spatial, and neurotransmitter-regulated pathways;• TME-associated mechanisms of resistance to immune checkpoint inhibitors, cellular therapies, vaccines, or cytokine-based treatments;• Biomarkers and patient-stratification strategies based on TME features;• Preclinical and clinical validation of rational combination therapies targeting the TME.Please note: Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic. Topic editors: Zhaohua Hou, Qiuju Han, Yang Yinli Source: https://www.frontiersin.org/research-topics/84598/neuroimmune-and-metabolic-regulation-of-the-tumor-microenvironment-in-immunotherapy