Psychological Stress Promotes Tumor Growth in Hepatocellular Carcinoma Models Through Myeloid Signaling

ABSTRACT Psychological stress has long been implicated in cancer progression, yet the underlying biological pathways remain incompletely understood. In particular, the influence of stress on myeloid cells remains poorly explored. Here, we demonstrate that restraint stress accelerates hepatocellular carcinoma (HCC) progression through coordinated regulation of macrophages and neutrophils. Across sexes and strains, stressed mice exhibited enhanced tumor growth accompanied by marked neutrophil infiltration and elevated expression of neutrophil‐attracting chemokines. Integrative analyses combining single‐cell transcriptomics and in vitro experiments identified macrophages as the dominant producers of these chemokines and revealed that β 2 ‐adrenergic receptor signaling drives Cxcl2 expression in response to stress‐related catecholamines. In parallel, neutrophils themselves were reprogrammed toward an immunosuppressive phenotype under stress. This phenotypic shift was already 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 define a coordinated neuroendocrine mechanism in which psychological stress remodels myeloid cell function through sympathetic and HPA axis signaling, thereby fostering 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.