Cadmium-induced activation of inflammatory cancer-associated fibroblasts-like cells enhances malignant phenotypes of lung cancer cells.

Cancer-associated fibroblasts (CAFs), as key stromal components of the tumor microenvironment (TME), exert profound influences on tumor progression by secreting cytokines, exosomes, and remodeling the extracellular matrix (ECM). Cadmium (Cd), a hazardous heavy metal, is strongly associated with lung carcinogenesis through environmental and occupational exposure. However, the molecular mechanisms underlying Cd-induced activation of fibroblasts and their functional contributions to lung cancer development remain poorly understood. Our study demonstrated that acute Cd exposure promoted the transformation of normal fibroblasts (MRC-5 cells) into an inflammatory CAFs-like (iCAFs) phenotype through upregulation of fibroblast activation protein (FAP). This Cd-driven FAP overexpression was accompanied by upregulated IL-6 and CCL2 release. Functionally, Cd-activated iCAFs-like cells significantly promoted the proliferation, migration, and invasion of lung cancer cell lines (H460 and A549) via paracrine signaling. Notably, FAP knockdown in MRC-5 cells using siRNA abrogated Cd-induced secretion of inflammatory factors and reversed the tumor-promoting effects of Cd-activated fibroblasts on cancer cells, establishing FAP as a central mediator of Cd-driven stromal reprogramming. These findings uncover a novel mechanism by which environmental Cd exposure exacerbates lung cancer progression through FAP-dependent fibroblast activation. Furthermore, they identify FAP as a potential therapeutic target for mitigating Cd-induced carcinogenesis, with implications for environmental toxin-associated cancer prevention and treatment.