Chronic Stress Stimulates Protumor Macrophage Polarization to Propel Lung Cancer Progression

Abstract Chronic psychological stress is often associated with manifestations of malignant diseases. Identification of modulators regulating the interaction between stress and tumorigenesis could provide potential strategies to ameliorate cancer progression. Here, we observed that chronic stress markedly promoted lung cancer progression. Analysis of the landscape of lncRNA expression indicated that lncRNA HIF1A-AS3 was upregulated in the stressed group and in lung cancer specimens compared to normal tissues. HIF1A-AS3 promoted proliferation and invasion of lung cancer cells both in vitro and in vivo. Mechanistically, HIF1A-AS3 translationally activated HIF-1α via direct interaction with YBX1, stimulating downstream signaling cascades. HIF-1α inversely stimulated HIF1A-AS3 transcription by directly binding to its promoter region. Investigation of the immune microenvironment revealed that macrophage depletion could efficiently abolish the tumor promoting effects of chronic stress. Both chronic stress and HIF1A-AS3 overexpression induced M2-like macrophage polarization in tumor tissues in mice. Conditioned medium from HIF1A-AS3 overexpressing lung cancer cells enhanced the mobility and phagocytic activity of human and murine macrophages. Targeting HIF1A-AS3/HIF-1α signaling, which was aberrantly upregulated in human lung cancer specimens and predictive of poor prognosis, counteracted chronic stress-induced lung cancer progression in vivo. In conclusion, the HIF1A-AS3/HIF-1α positive feedback loop mediates chronic stress-induced lung cancer growth through functional reprogramming of tumor-associated macrophages, suggesting that this axis may serve as a promising diagnostic and therapeutic target for patients with lung cancer suffering from psychological stress.