Chronic social defeat stress accelerates lung cancer progression and induces hippocampal metabolic dysregulation in a duration-optimized comorbid model.

[UNLABELLED] Chronic social defeat stress (CSDS) is a commonly used mouse model of depression, yet lung cancer - CSDS combined model remains underexplored. Research on the duration of CSDS to induce persistent depressive phenotypes is also relatively limited and calls for further study. This study aims to elucidate the relationship between stress duration and depressive severity, and to clarify the neurobiological links between tumor burden and depression-like behaviors. A combined lung cancer - CSDS mouse model was established by integrating stress exposure and Lewis lung carcinoma implantation. Depressive-like behaviors were assessed using the open field test, social interaction test, tail suspension test, and forced swimming test. Pathological changes in tumor and hippocampal tissues were examined via H&E staining. Targeted metabolomics (LC-MS) was used to quantify hippocampal neurotransmitter levels. Depressive-like behaviors emerged after 7 days of CSDS and were more prominent in the 10- and 14-day groups. Mice exposed to ≥ 10-day CSDS exhibited no remission of depression within 30 days. In the comorbid model, CSDS significantly accelerated tumor progression. Tumor burden exerted an independent, additive negative impact on behavior, superimposed on the stress effect. Metabolomic analyses revealed the dysregulation of hippocampal metabolic profiles: (1) a synergistic effect of stress and tumor burden reflecting a shift of tryptophan metabolism toward the inflammatory kynurenine pathway (increased Kyn/Trp ratio); (2) a tumor-driven accumulation of energy-related and excitatory metabolites (succinic and aspartic acid); and (3) an additive depletion of monoamine precursors (tryptophan, tyrosine, phenylalanine) and functional amino acids. CSDS induced social avoidance and behavior deficits in a duration-dependent manner, with ≥ 10-day exposure resulting in more persistent depressive phenotypes. In the comorbid model, stress accelerates tumor growth, and the tumor burden independently compromises neurochemical homeostasis. The specific disruption of the tryptophan-kynurenine axis and tumor-driven mitochondrial/excitatory stress highlights a lung-brain metabolic interface as a potential therapeutic target.

[GRAPHICAL ABSTRACT] [Image: see text]

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s11011-026-01792-1.