Pakistan Journal of Pharmaceutical Sciences

Abstract: Background: The clinical application of dihydroartemisinin (DHA) is limited by its pharmacokinetic profile, making high in vitro concentrations clinically unattainable. Its effects at physiologically relevant low doses, especially in the complex tumor microenvironment (TME), are poorly understood. Objectives: This study investigated how clinically attainable low-dose DHA affects the efficacy of cisplatin in lung cancer in both monoculture and macrophage co-culture conditions, thereby uncovering a novel TME-dependent mechanism. Methods: Using human lung cancer cells and THP-1-derived macrophages, we conducted viability and invasion assays and measured IL-6 levels in both monoculture and co-culture systems. The effects of DHA on cisplatin sensitivity and invasion were evaluated, and rescue experiments using recombinant IL-6 and neutralizing antibodies were performed. Results: Low-dose DHA antagonized cisplatin cytotoxicity in monoculture but potently enhanced cisplatin-induced cell death after co-culturing with macrophages. Mechanistically, this sensitization was mediated via DHA-mediated inhibition of IL-6 secretion by macrophages. Adding exogenous IL-6 partly reversed this effect, while an IL-6 neutralizing antibody mimicked this effect. Furthermore, cisplatin paradoxically promoted cancer cell invasion by inducing IL-6 release from macrophages, which was efficiently blocked by low-dose DHA via the same pathway. Conclusion: At clinically relevant concentrations, the principal antitumor property of DHA lies in TME modulation rather than direct cytotoxicity. By inhibiting macrophage-derived IL-6, DHA simultaneously mitigated chemoresistance and invasion, resensitizing lung cancer cells to cisplatin. These findings provide a mechanistic rationale for combining DHA with platinum-based chemotherapy.