Abstract
Systemic inflammation is associated with poor outcomes in gastroesophageal adenocarcinoma (GEA), but how it contributes to disease progression remains unclear. We investigated retinoic acid receptor-related orphan receptor gamma (RORγ) as a regulator of tumour-conditioned myeloid responses. In treatment-naive GEA patients, elevated circulating neutrophil-to-lymphocyte ratio (cNLR) tracked with circulating RORγ positive neutrophils and tumoural spatial organization of RORγ positive myeloid cells, rather than neutrophil abundance. In syngeneic tumour models, pharmacologic RORγ inverse agonism altered marrow progenitor composition before tumour-growth divergence and remodeled myeloid organization across bone marrow, tumour and lung despite no endpoint change in circulating neutrophil proportions, which did not capture the earlier marrow response or subsequent tumour trajectory. RORγ perturbation enhanced longitudinal tumour control with PD-L1 blockade, whereas effects on metastatic establishment depended on tumour conditioning and treatment timing. These findings identify RORγ associated myeloid programming as a therapeutically tractable, context-dependent regulator linking systemic inflammation, hematopoiesis, tissue immune organization, and cancer progression.