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Depression remodels tumor microenvironment to drive tumor progression: Bio-behavioural signalling pathways and clinical interventions.

Mengkai Ge,Wenjin Zhang,Wenlong Zhang,Zixuan Zhang,Xiaobei Zeng,L. Deng,Meiyun Wen,Xiaorong Lu,Xian Shen,Zhiyong Li,Guangjiang Shi

Published 2025 in Journal of Advanced Research

ABSTRACT

BACKGROUND Depression, chronic stress, fear, and anxiety have been implicated as major risk factors in tumor growth, invasion, and metastasis. These psychological conditions stimulate the secretion of neurotransmitters and stress hormones through prolonged activation of the fight-or-flight response. The arousal of stress-related systems, such as the hypothalamic-pituitary-adrenocortical axis and the sympathetic nervous system, induces physiological alterations. Consequently, stress-associated mediators suppress antitumor immune responses, enhance the release of inflammatory cytokines, and promote tumor cell migration and survival within an altered tumor microenvironment through diverse signaling pathways. AIM OF REVIEW This review highlights recent advances in understanding how depression and chronic stress regulate tumor growth, angiogenesis, invasion, and metastasis. We further discuss how stress response systems remodel the tumor microenvironment to promote cancer progression, providing insights into the interface between behavioral and biological mechanisms and identifying potential therapeutic targets. KEY SCIENTIFIC CONCEPTS OF REVIEW We emphasize the rationale and importance of developing pharmacological interventions to inhibit tumor progression and enhance the efficacy of conventional therapies and immunotherapies in patients with cancer-associated depression. Moreover, we discuss emerging pharmacological strategies with the potential to prevent stress-related cancer progression.

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