This study aimed to investigate the anti-tumor effects and mechanisms of propranolol (Prop) in mice with colorectal cancer (CRC) combined with chronic stress, as well as its potential impact when used in combination with high-mobility group nucleosome-binding domain 1(HMGN1). The findings are intended to provide a novel therapeutic strategy and theoretical basis for cancer patients with comorbid psychological stress or depression. Chronic stress facilitated colorectal cancer progression in both in vivo and in vitro models. Propranolol inhibited cell proliferation and colony formation while inducing apoptosis.
A single intratumoral injection of propranolol achieved a 100% complete tumor regression rate (9 of 9 mice) in both the CT26 murine colorectal cancer model subjected to chronic stress and the control model, without affecting body weight or physiological status, while inducing durable tumor-specific immune memory up to 80 days post-treatment. Recurrent inoculation of CT26 cells on the same or contralateral side failed to establish tumors in completely responded, whereas allogeneic 4T1 cells grew normally. Cross-model supplementary data demonstrated the tumor-suppressive effects of propranolol in other neoplasms. In combination therapy, intraperitoneal administration of propranolol enhanced HMGN1's anti-tumor efficacy, inhibiting tumor growth with significantly greater effects under chronic stress compared to controls.
Epinephrine suppressed immune cell activation and triggered stress-related neuroendocrine changes, which were partially reversed by propranolol. We demonstrated the anti-tumor potential of β-adrenergic receptor (β-AR) blockade and elucidated the antitumor effects and underlying mechanisms of its antagonist propranolol. Combination immunotherapy broadly enhanced immune function under chronic stress conditions and exhibited strong potential for clinical translation.
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