Fig. 6.

CYP19A1/CYP2D6-driven immune dysregulation and carcinogenic mechanism of DNP via T-cell reprogramming. (A) The expression abundance of CYP19A1 and CYP2D6 in different cell types was analyzed in the hHNSCC single-cell dataset. Both genes were significantly expressed in the malignant and CD8⁺ Tex cell populations. (B) Immune infiltration analysis revealed that CYP19A1 was significantly highly expressed, whereas CYP2D6 was significantly expressed at low levels in T-cell CD8⁺ and T-cell follicular helper subsets (p < 0.01), which was consistent with previous experimental results. (C) Mechanistic inference diagram: After DNP enters the body, it resides in the nasopharyngeal region and is activated by the CYP enzyme system in the form of dealkylation. On the one hand, it covalently binds with the amino groups on nucleotides in DNA, causing DNA mutations or chromosomal aberrations during cell division, thereby accelerating the carcinogenesis process. On the other hand, it promotes the expression of CYP19A1 and inhibits the expression of CYP2D6, driving the continuous differentiation of stem-like PD-1^lo CD8⁺ T cells into dysfunctional PD-1^hi CD8⁺ Tex cells, which eventually undergo apoptosis. This process reduces the immune system’s ability to surveil and eliminate tumor cells