Benzo[a]pyrene (BaP), a toxic polycyclic aromatic hydrocarbon and exogenous ligand of the aryl hydrocarbon receptor (AhR), has been implicated in immune evasion mechanisms in lung adenocarcinoma (LUAD). This study explores how BaP influences the expression of immune checkpoints, particularly PD-L1 and ICOSL, and investigates the underlying role of AhR and tryptophan (Trp) metabolism in this process.

Lung epithelial cell lines (BEAS-2B and H1975) exposed to BaP exhibited significant upregulation of PD-L1 and ICOSL at both the mRNA and surface protein levels, with AhR identified as a key regulator. The contribution of Trp metabolism to BaP-induced immune evasion was assessed by culturing cells in Trp-depleted and Trp-supplemented conditions, inhibiting Trp-catabolizing enzymes (TDO2 and IDO1), and analyzing their expression. Notably, TDO2 inhibition effectively reduced PD-L1 and ICOSL expression, underscoring the pivotal role of Trp metabolism in immune checkpoint regulation. Further clinical data analysis linked elevated TDO2 expression in LUAD to poor patient prognosis. In an orthotopic LUAD mouse model, pharmacological inhibition of TDO2 suppressed tumor growth, immune checkpoint expression, and Trp metabolism, reinforcing its therapeutic potential.

These findings elucidate a BaP-driven immune evasion mechanism in LUAD mediated by the AhR/TDO2 axis. Targeting TDO2 offers a promising strategy to counteract immune suppression and enhance anti-tumor immunity, paving the way for novel immunotherapeutic approaches in lung cancer treatment.