Rethinking the microenvironment's role in chemical-induced malignancy.

Why and how does cancer start? Building from a Symposium at the 2025 Society of Toxicology meeting, we convened a group of international experts to answer this seemingly simple question. As experimental evidence has evolved, perspectives on cancers' origins have shifted from the accumulation of DNA mutations in single cells to complex processes involving signals from an altered tissue microenvironment which promote tumorigenesis. Carcinogen exposures impact the biology of the microenvironment in complex and tissue-specific ways. These changes can include the infiltration of inflammatory cells that produce growth factors, neo-angiogenesis, morphological changes, and immune tolerance that avoids immune-mediated elimination. In this in-depth review, we discuss the evidence linking chemical-driven microenvironmental changes in the development of a range of solid and liquid tumors. We discuss specific phenotypic alterations, such as selection pressure driving clonal expansion and cellular plasticity and reacquisition of stem cell states, linked to carcinogen-induced changes in the microenvironment. We describe assays and biomarkers which can allow us to experimentally assess links between chemical exposures, the microenvironment, and cancer phenotypes. We end by discussing how understanding the role of the microenvironment and malignancy in toxicology is essential for accurate cancer hazard evaluation, development of next-generation risk assessment frameworks, identifying new strategies for cancer prevention, and improving patient care.