Oral Administration of Itraconazole Induces M1 Polarization of Tumor-associated Macrophages in Gynecological Cancer
Itraconazole (ITZ), an antifungal agent with reported anticancer properties, has been shown to induce phenotypic repolarization of tumor-associated macrophages (TAMs) from an M2-like to an M1-like phenotype Nineteen patients with cervical, vaginal, or vulvar cancer received oral ITZ (20 ml of 10 mg/ml solution, twice daily) in a window-of-opportunity trial (jRCTs051190006). Tumor response was assessed using transvaginal ultrasound. Paired tumor biopsy specimens obtained before and after ITZ treatment from patients with ≥20% tumor reduction within two weeks of ITZ treatment were analyzed by immunohistochemistry using anti-CD163 and anti-CD86 antibodies to identify M2-like and M1-like TAMs, respectively. Quantitative image analysis was performed using the Vectra3 system and inForm software. Among the 19 patients, four [21.1%; 95% confidence interval (CI)=6.1-45.6%] showed ≥20% tumor reduction within two weeks of ITZ treatment, including one patient who achieved complete macroscopic regression. Immunohistochemical analysis of paired tumor samples from the remaining three responders demonstrated an increase in CD86 single-positive and CD163/CD86 double-positive TAMs after ITZ administration. ITZ treatment was associated with increased infiltration of M1-like TAMs in cancer tissues, suggesting an immunomodulatory effect. These findings support further investigation of ITZ as a potential adjunct in cancer therapy.