Distinct Systemic Metabolic Remodeling and Neurobehavioral Deterioration in Chemotherapy‐Treated Lung Cancer Models

ABSTRACT Peripheral tumors and chemotherapy reshape host physiology, yet model selection for cancer‐related neurobehavioral deterioration often remains empirical. In lung cancer, this deterioration often presents clinically as a somatic‐psychological symptom cluster that includes fatigue, pain‐related symptoms, sleep disturbance, and distress. We asked whether chemotherapy‐treated subcutaneous and orthotopic Lewis lung carcinoma models reproduce a comparable symptom‐related state or instead reflect distinct systemic and neurobehavioral contexts. Male C57BL/6J mice bearing subcutaneous tumors (STCG) or orthotopic tumors (OTCG), together with normal controls, were followed through chemotherapy using behavioral measures of fatigue‐related performance, pain/discomfort responses, sleep‐related responses, center‐zone exploration and passive coping. These trajectories were interpreted alongside plasma metabolic profiles and targeted peripheral and brain pathological readouts. The two models diverged. STCG preserved survival and showed an active sickness‐like pattern, including impaired rotarod performance, delayed sleep onset and a trend toward shortened thermal response latency. OTCG showed survival attrition, late‐stage systemic deterioration, reduced thermal nociceptive responsiveness, prolonged pentobarbital‐induced sleep duration and stronger behavioral suppression. Plasma metabolomics revealed broader remodeling in OTCG, involving ketone body, glutathione, one‐carbon and redox‐related pathways. Both tumor‐bearing models showed peripheral oxidative stress and brain alterations involving Claudin‐5, glial activation and synaptic markers. Exploratory within‐model networks identified fatigue‐related performance as a highly connected node, with differing behavioral and biological associations. These findings suggest that the two models capture complementary but non‐interchangeable metabolic and neurobehavioral states under the tested chemotherapy conditions.