Chemotherapy-induced neuropathic pain (CIPN) remains one of the most debilitating side effects of cancer treatment, yet its mechanisms are poorly understood. Using a novel orthotopic colon cancer model, we discovered that tumors alone can trigger “subclinical” neuronal damage - characterized by intraepidermal nerve fiber loss, mitochondrial dysfunction, and altered calcium homeostasis - without overt pain symptoms. These paraneoplastic changes may sensitize the nervous system and dramatically worsen CIPN once chemotherapy begins. The observed robust inflammatory changes might also affect the central nervous system. Our findings highlight a previously unrecognized tumor-nerve interaction that could explain why some patients develop severe, therapy-resistant CIPN, and open new avenues for future research and personalized prevention strategies.