Psychological stress promotes hepatocellular carcinoma progression via β2-adrenergic signaling in macrophages and glucocorticoid-driven neutrophil immunosuppression

In parallel, neutrophils themselves were reprogrammed toward an immunosuppressive phenotype under stress. This phenotypic shift was evident in bone marrow neutrophils, where activation of the hypothalamic–pituitary–adrenal (HPA) axis led to corticosterone-driven, glucocorticoid receptor–dependent induction of an immunosuppressive gene. These findings uncover a coordinated neuroendocrine mechanism in which psychological stress remodels myeloid cell function through sympathetic and HPA axis signaling, thereby establishing an immunosuppressive tumor microenvironment that promotes HCC progression.

While pharmacologic blockade of either axis may mitigate stress-driven tumor growth, our findings suggest that non-pharmacological stress-reduction strategies could represent a valuable complementary approach in managing HCC progression.