Not All Carcinogens Are Directly Mutagenic: A Holistic View of the Environmental Exposure–Cancer Connection

Cancers, a leading cause of morbidity and mortality worldwide, are undergoing notable shifts in incidence patterns. Cancer subtypes generally associated with advancing age are now increasingly being diagnosed in younger populations, while gender disparities in cancer susceptibility have fluctuated across various malignancies. Some cancer subtypes previously confined to specific geographical populations are now globally prevalent. Remarkably, these changing patterns of cancer incidence have occurred despite relatively stable mutational landscapes specific to each cancer type, highlighting the role of environmental exposures (exposomes) as potential drivers of these trends. Intriguingly, evidence suggests that the exposome may exert some of its influence through nonmutagenic mechanisms, although the precise ways in which environmental carcinogens trigger or promote cancer development remain poorly understood. This review summarizes the current understanding of the mutagenic and nonmutagenic mechanisms through which carcinogens, including tobacco smoke, air pollutants, metals, diet, and alcohol, impact cancer development, as this may help inform precision prevention and public health policy.