Genotype-to-Microenvironment Signaling Axes in Cancer

This Research Topic focuses on how tumor genetic and genomic programs shape the tumor microenvironment (TME) through defined signaling circuits that drive immune escape, metabolic adaptation, tumor progression, and variable therapy response. We invite submissions that move beyond descriptive TME profiling and instead establish testable, mechanism-based links between tumor genotype, signaling activity, microenvironmental remodeling, and clinical outcomes, with clear translational relevance for cancer diagnostics, prognostics, and treatment selection.Many cancers employ microenvironmental strategies—such as immune exclusion, myeloid skewing, T-cell dysfunction, stromal remodeling, and metabolic rewiring—that are not random or purely context-driven. Instead, these phenotypes often arise from somatic alterations, copy-number changes, epigenomic reprogramming, or genome-defined pathway activation states within malignant cells. The aim of this Research Topic is to consolidate state-of-the-art work that links these tumor-intrinsic genomic states to microenvironmental consequences and therapeutic vulnerabilities, including rational combination strategies. We particularly welcome studies that integrate cancer genomics and oncogenomics with modern experimental and computational approaches, such as multi-omics integration, single-cell and spatial profiling, and functional genomics. Suitable submissions may address, for example: • Genomic and epigenomic determinants of immune infiltration and immune exclusion.• Immunogenomic mechanisms of immune recognition and escape, including antigen presentation and interferon signaling defects.• Cytokine/chemokine signaling programs encoded by tumor genomic states that control immune trafficking, spatial segregation, and “hot–cold” transitions.• Pathway-node crosstalk underlying these states—such as RTK–RAS–MAPK, PI3K–AKT–mTOR, JAK–STAT, NF-κB, TGF-β, Wnt/β-catenin, and Hippo–YAP/TAZ—and their mechanistic consequences for immune and stromal remodeling.• Immunometabolic coupling associated with tumor pathway activation, including lactate, hypoxia, adenosine, and nutrient competition across glucose, lipid, and amino acid metabolism.• Tumor–stroma signaling loops that are initiated or stabilized by tumor genetic programs, including CAF/ECM remodeling, mechanotransduction, and vascular barriers that limit immune access or drug response.Submissions should provide mechanistically grounded insights and explicitly state implications for biomarker development, therapeutic response prediction, and therapy optimization, including combination strategies. We encourage work supported by independent cohort verification and/or experimental validation that demonstrates causality rather than correlation.We welcome original research, methods papers, reviews, and perspectives. Manuscripts based primarily on re-analysis of existing public datasets are not considered unless they include substantive methodological innovation and robust verification using independent datasets and/or experimental validation. Topic editors: Fahui Liu, Jikui Guan, Qiming Gong Source: https://www.frontiersin.org/research-topics/78063/genotype-to-microenvironment-signaling-axes-in-cancer