Supraphysiologic Testosterone Induces Ferroptosis and Activates Immune Pathways through Nucleophagy in Prostate...

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• Androgen deprivation therapy (ADT) is a standard prostate cancer treatment.
• A subset of prostate cancers exhibits paradoxical growth inhibition with supraphysiologic testosterone (SupraT).

Purpose of the Study:

• To investigate the mechanism by which SupraT inhibits prostate cancer growth.
• To elucidate the role of autophagy and immune signaling in SupraT-mediated growth inhibition.

Main Methods:

• Experimental administration of SupraT to prostate cancer models.
• Analysis of autophagy-mediated processes (ferritinophagy, nucleophagy).
• Assessment of nucleic acid sensor activation and downstream immune signaling (NFκB, chemokines, cytokines).
• Evaluation of immune cell infiltration in xenograft and patient tumor samples.

Main Results:

• SupraT induced ferritinophagy and nucleophagy in sensitive prostate cancer cells.
• Activated nucleic acid sensors converged on NFκB, driving immune signaling.
• Secreted chemokines and cytokines promoted cytotoxic immune cell migration to tumors.
• SupraT demonstrated growth inhibition in a subset of prostate cancer.

Conclusions:

• Supraphysiologic testosterone inhibits a subset of prostate cancer via activation of cytoplasmic nucleic acid sensors.
• This inhibition is mediated by parallel autophagy-dependent processes: ferritinophagy and nucleophagy.
• SupraT treatment triggers tumor cell-intrinsic immune signaling, enhancing anti-tumor immunity.