Tumor‑associated glucocorticoid inhibition by mifepristone reduces polymorphonuclear myeloid‑derived suppressor cells and promotes antitumor immunity in triple‑negative breast cancer‑bearing mice.

Triple‑negative breast cancer (TNBC) is a highly malignant subtype with limited effective treatment options. The present study investigated the antitumor immune effects of mifepristone, a glucocorticoid receptor antagonist, using subcutaneous, orthotopic and experimental lung metastasis mouse models transplanted with 4T1 TNBC cells. Mifepristone treatment suppressed tumor growth and metastasis, leading to improved overall survival. Flow cytometric analysis of the spleen revealed decreased polymorphonuclear myeloid‑derived suppressor cells (PMN‑MDSCs) and increased T cells in the spleen, accompanied by enhanced T‑cell activity assessed . Similar immune alterations were observed in tumor‑infiltrating cells, indicating enhanced intratumoral T‑cell responses. These results suggested that the antitumor effects of mifepristone may be partly mediated by reducing PMN‑MDSCs and restoring antitumor immunity. In tumor‑bearing mice, plasma levels of corticosterone, the major murine glucocorticoid, were elevated. In experiments using bone marrow and splenocytes, corticosterone promoted PMN‑MDSC induction and suppressed T‑cell activity, and these effects were reversed by mifepristone. Thus, mifepristone may modulate immune cell dynamics by inhibiting systemic corticosterone. To elucidate the mechanism underlying plasma corticosterone elevation, the corticosterone‑generating capacity of 4T1 cells was analyzed by exposing them to 11‑dehydrocorticosterone (DHC). The results demonstrated that 4T1 cells possessed the ability to convert the inactive form of glucocorticoid, DHC, into its active form, corticosterone, through the enzymatic activity of 11β‑hydroxysteroid dehydrogenase type 1 (11β‑HSD1). Furthermore, treatment with carbenoxolone (a non‑selective 11β‑HSD1 inhibitor) in tumor‑bearing mice decreased plasma corticosterone levels, suppressed tumor growth and produced immune changes similar to mifepristone treatment. These findings suggested that the elevated plasma corticosterone levels in tumor‑bearing mice may be mediated by 11β‑HSD1‑dependent corticosterone production, and that this mechanism was likely induced by 4T1 cells. In conclusion, the present study indicated that 4T1 cells possess corticosterone‑generating capacity through 11β‑HSD1, promoting systemic corticosterone elevation and tumor growth. Mifepristone may restore antitumor immunity, likely by reducing PMN‑MDSCs through systemic corticosterone blockade. These insights could inform the development of novel therapeutic approaches for TNBC.