Objectives Understanding the mechanisms by which an exposure causes cancer can be critical to establishing causality and to developing successful prevention/intervention strategies. Multiple mechanisms underlying the carcinogenicity of night shift work have been proposed, including several novel ones in recent years, though specific mechanistic links remain uncertain.

Methods Novel mechanisms for the carcinogenicity of night shift work will be reviewed. In the context of these mechanisms, the methodologic limitations that continue to plague human mechanistic studies of night shift work will also be discussed.

Results Multiple animal studies and some human mechanistic studies have pointed to suppressed DNA damage repair, epigenetic impacts and gut dysbiosis as novel mechanisms by which night shift work may cause cancer. Human mechanistic studies continue to suffer from multiple limitations such as small sample sizes, poorly defined shift schedules, inappropriate timing of biospecimen collection relative to conduct of night shift work and inadequate consideration of diurnal variation in biomarker measures.

Conclusions While there is compelling evidence for multiple novel mechanisms underlying the potential carcinogenicity of night shift work, additional high quality human mechanistic studies are needed to establish the relevance of these mechanisms.