Chronic Stress Stimulates Protumor Macrophage Polarization to Propel Lung Cancer Progression

Chronic psychologic 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. In this study, we observed that chronic stress markedly promoted lung cancer progression. Analysis of the landscape of long noncoding RNA expression indicated that long noncoding RNA HIF1A-AS3 was upregulated in the stressed group and in lung cancer specimens compared with normal tissues. HIF1A-AS3 promoted the proliferation and invasion of lung cancer cells both in vitro and in vivo. Mechanistically, HIF1A-AS3 translationally activated hypoxia-inducible factor-1α (HIF1α) via direct interaction with YBX1, stimulating downstream signaling cascades. HIF1α 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 macrophages mobility. Macrophages exhibited suppressed phagocytic activity against HIF1A-AS3-overexpressing tumor cells. Targeting HIF1A-AS3/HIF1α 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/HIF1α 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 psychologic stress.

Chronic stress facilitates lung cancer immune evasion by inducing M2-like macrophage polarization, supporting the potential of combination therapies targeting both tumor cells and the immune microenvironment for treating stress-related cancers.