Chronic stress promotes colorectal cancer progression by inducing M2 macrophage polarization and activating the CCL2-CCR2 axis

Chronic stress is associated with poor prognosis in colorectal Cancer (CRC), but the underlying immune mechanisms remain poorly defined. This study investigates how β-adrenergic signaling, a key component of the stress response, modulates the tumor microenvironment. We demonstrate that stressed CRC patients have elevated serum CCL2, and high tumoral expression of CCL2 and its receptor CCR2 predicts poor survival. Single-cell analysis reveals that within the tumor microenvironment of colorectal Cancer, macrophages constitute the primary subset of immune cells responsible for CCL2 secretion. Mechanistically, we demonstrate that stimulating macrophages with isoproterenol, a well-established in vitro method to mimic chronic stress signaling, induces their polarization toward an M2-like phenotype and significantly increases CCL2 secretion. Functionally, conditioned media from these "stressed" macrophages enhanced CRC cell proliferation and invasion in a CCR2-dependent manner, an effect abrogated by pharmacological CCR2 blockade. Collectively, our findings pinpoint the CCL2-CCR2 pathway as the central mediator of a 'stress-macrophage-tumor' axis, validating it as a key therapeutic target to intercept CRC progression driven by a chronic stress state elicited by β-adrenergic activation.