Benzo[a]pyrene (B[a]P) is a recognized carcinogen for lung cancer, but its associations with digestive system cancers (DSCs) remain unclear and the common carcinogenic mechanisms are not fully understood. We conducted five nested case-control studies within the Dongfeng-Tongji cohort, including esophageal (EC, n = 58), gastric (GC, n = 103), colorectal (CRC, n = 220), hepatic (HC, n = 117), and pancreatic cancers (PC, n = 45). For each case, two sex and age ( ± 5 years) matched healthy controls were selected. We observed significant J-shaped associations between plasma concentrations of benzo[a]pyrene diol epoxide-albumin (BPDE-Alb) adducts and five DSCs (all P for non-linear <
0.05). The subjects with high BPDE-Alb exposure exhibited a separate 2.19, 2.14, 1.67, 2.40, and 1.78-fold incident risks of EC, GC, CRC, HC, and PC (95% CI: 1.00-4.83, 1.24-3.67, 1.15-2.43, 1.48-3.90, and 0.71-4.47, respectively) than those with low exposure. Furthermore, the adverse outcome pathway (AOP) network indicated five molecular initiation events and 18 subsequent key events, particularly, the alterations in receptors of AhR, EGFR accompanied by regulations of cell proliferation and apoptosis pathways (e.g., PI3K-Akt, TNF signaling) may facilitate common carcinogenic processes. Our findings revealed the positive associations of B[a]P exposure with five DSCs, and the dysregulation of proliferation and apoptosis may initiate B[a]P-induced cancer development.