A Critical Perspective on the Role of Thirdhand Smoke in Tumorigenesis: Initiator or Promoter.

Thirdhand smoke (THS), lingering tobacco residues on surfaces and in dust after smoking, has emerged as a growing public health concern. While the carcinogenic risks of first- and secondhand smoke are well established, the tumorigenic potential of THS remains inadequately understood. In this perspective, we systematically review the known THS-related compounds together with the existing biological findings to provide evidence on the carcinogenic potential of THS. We assess the role of THS in the context of the classic multistage model of tumorigenesis to address whether THS acts primarily as a tumor initiator, or as a promoter, or both. We also discuss methodological challenges in isolating the effects of THS on human health and the importance of animal models and outline emerging strategies for risk assessment, biomarker discovery, and precision prevention. This Perspective is the first to integrate chemical, toxicological, and mechanistic evidence to evaluate the carcinogenic potential of THS within the framework of the multistage model of tumorigenesis, offering a new conceptual foundation for understanding the role of THS in human cancer etiology, which is crucial for informing public health policies aimed at mitigating its impact.