Report: 5-FU and Imiquimod Combo May Offer Enhanced Actinic Keratosis Clearance

Key Takeaways

• Dual use of 5-FU and imiquimod appears to yield greater efficacy than either agent alone in treating actinic keratoses (AK).

• The combination therapy targets direct cytotoxic and immune-mediated pathways.

• Enhanced absorption of imiquimod through 5-FU–compromised skin may further potentiate treatment, the authors said.

Combining 5-fluorouracil (5-FU) and imiquimod may enhance therapeutic efficacy for actinic keratoses (AK), according to emerging data.

"To date, the combination of 5-FU and imiquimod, 2 of the most used monotherapies, remains underexplored," the authors wrote. Their completed literature review located just two additional investigations evaluating the 5-FU/imiquimod combination. All available data, according to the authors, suggest that the concurrent use of 5-FU and imiquimod may be more effective than monotherapy.

5-FU produces its antineoplastic effect through the inhibition of thymidylate synthase, which the authors explained disrupts DNA replication/repair, as well as compromising nucleic acid synthesis and function. Meanwhile, imiquimod acts via toll-like receptor (TLR) 7 and 8 activation, leading to downstream NF-κB signaling, as well as the upregulation of pro-inflammatory cytokines (IFN-α, TNF-α, IL-6, and IL-12). This further enhances the maturation and activity of dendritic cells, natural killer cells, and cytotoxic T cells, the authors noted.

The authors also noted that distinct pathways likely produce synergistic effects. The DNA damage and apoptosis triggered by 5-FU increase tumor immunogenicity, which imiquimod can exploit by amplifying immune-mediated clearance. Additionally, intensifying the local immune response is intensified due to 5-FU–induced epidermal disruption, possibly facilitating deeper penetration and greater bioavailability of imiquimod.

"Overall, the combination of 5-FU and imiquimod holds significant promise as a synergistic therapy for AK/field cancerization therapy by simultaneously maximizing the number of pathways for cell death and harnessing the power of the immune system for cellular clearance." the authors wrote.

Source: Majidian S, et al. J Drugs Dermatol. 2025. doi:10.36849/JDD.S1545961625P8756X