Colorectal cancer cells hijack a brain-gut polysynaptic circuit from the lateral septum to enteric neurons to sustain tumor growth.

The bidirectional interaction between the brain and peripheral tumors is critical but poorly understood. Here we show GABAergic neurons in the lateral septum, a key brain region implicated in emotional regulation, connect via a polysynaptic circuit to enteric cholinergic neurons that send nerve fibers into the tumor microenvironment, which were then hijacked by colorectal cancer cells to sustain tumor growth in mice. Functionally, activation of this septo-enteric circuit induces GABA release from enteric cholinergic neurons, which in turn activates epsilon-subunit-containing GABA_A receptors on tumor cells. Notably, chronic restraint stress potentiates activity within this circuit, exacerbating tumor progression. Clinically, patients with colorectal cancer exhibiting elevated neuronal activity in the septal region present with larger primary tumors. Collectively, our findings uncover a stress-sensitive septo-enteric polysynaptic pathway exploited by cancer cells to promote tumor growth, underscoring the previously unrecognized role of lateral septum-mediated neural circuitry and psychological stress in cancer progression.