Dysregulated energy homeostasis at the crossroads of cancer-depression comorbidity: A brain-body-tumor interaction perspective.

Cancer-depression comorbidity (CDC), the bidirectional and clinically consequential coexistence of cancer and major depressive disorder, represents a particularly severe and prognostically adverse clinical state. Compared with either condition alone, patients with CDC show poorer adherence to anticancer treatment, reduced quality of life, and increased all-cause and cancer-specific mortality. Epidemiological evidence suggests that depression may raise long-term risk for several cancers, while cancer itself frequently precipitates depressive syndromes, supporting a reciprocal relationship between the two conditions. In this Review, we propose that CDC is best conceptualized not as two separate entities but as a unified disorder of systemic energy homeostasis. We present a brain-body-tumor interaction perspective and outline a tri-level regulatory model linking central energy-sensing circuits and neuroendocrine control with peripheral metabolic allocation and tumor microenvironmental demands. Central to this model is the dysregulated energy homeostasis, wherein chronic stress, inflammation, and tumor burden progressively erode bioenergetic capacity across the brain and body. Mitochondrial dysfunction serves as the key integrator and executor of these insults, linking cellular ATP failure to systemic catabolism, immune dysfunction, and depressive phenotypes. Finally, we highlight that therapies targeting energy homeostasis, including mitochondrial support, metabolic and immunometabolic reprogramming, nutritional or microbiome based approaches, and behavioral interventions, may provide dual benefits for both cancer control and mood regulation in CDC.