Benzo[a]pyrene carcinogenicity across organs and cancer stages: Molecular mechanisms and interactions with co-exposed...

Benzo[a]pyrene (BaP) is a persistent combustion-derived polycyclic aromatic hydrocarbon (PAH) that causes widespread human exposure. BaP has been classified as a Group I carcinogen by the International Agency for Research on Cancer (IARC), with sufficient evidence supporting its carcinogenicity in multiple target organs, primarily through metabolic activation-mediated genotoxicity. Increasing evidence indicates that BaP and its metabolites also contribute to tumor promotion and progression by regulating cellular survival, metabolic adaptation, malignant transformation, intercellular communication, and immune microenvironmental remodeling. In addition, BaP may interact with co-occurring environmental chemicals to produce synergistic or antagonistic carcinogenic effects, yet the mechanisms underlying these interactions remain insufficiently defined. Existing reviews have mainly focused on specific mechanisms or exposure settings, limiting a multidimensional understanding of BaP carcinogenicity under complex environmental exposure scenarios. Here, we synthesize classical evidence and recent advances in BaP-induced carcinogenicity across four interconnected dimensions: cancer occurrence in different tissues, the role of BaP in cancer initiation, promotion, and progression, key molecular mechanisms, and co-carcinogenic interactions with other chemicals. This review highlights that BaP carcinogenicity extends beyond genotoxic initiation and involves stage-dependent, tissue-specific, and interaction-driven processes. We further propose future priorities, including gaining a deeper understanding of tissue-specific regulatory networks, applying omics-based approaches to define carcinogenic signatures, and elucidating interaction mechanisms under realistic chemical co-exposure scenarios. This synthesis provides a framework for more mechanism-informed assessment of BaP-related environmental health risks and mixture carcinogenicity.