Cigarette smoke-mediated YTHDC2 suppression drives macrophage senescence and a tumor-promoting microenvironment in lung cancer

Cigarette smoke is a leading cause of lung cancer, promoting disease progression through remodeling of the immune microenvironment. This study explores the impact of cigarette smoke exposure on the m⁶A reader YTHDC2, its role in inducing macrophage senescence, and the consequent formation of a tumor-supportive inflammatory niche in lung cancer. Single-cell RNA sequencing of lung cancer tissues revealed an enrichment of senescent macrophages with decreased YTHDC2 expression in smokers compared to non-smokers. In vitro experiments showed that cigarette smoke extract (CSE) suppressed YTHDC2 expression in macrophages, resulting in enhanced cellular senescence, increased secretion of pro-inflammatory cytokines and M2-like polarization. Overexpression of YTHDC2 attenuated macrophage senescence by regulating RPS8, thereby limiting the formation of a tumor-promoting microenvironment. In vivo studies using a cigarette smoke-exposed lung cancer model confirmed the role of YTHDC2 in smoke-induced immune microenvironment modulation and tumor progression. These findings identify YTHDC2 as a critical regulator of smoke-induced macrophage senescence and the tumor-promoting microenvironment, providing a potential therapeutic target for lung cancer in smokers.