Testosterone, the principal androgen in humans, plays an essential role in maintaining physiological homeostasis. In recent years, accumulating evidence has implicated testosterone in the progression of diverse malignancies, underscoring its context-dependent roles in tumor biology. A series of studies suggest that testosterone can act through canonical androgen receptor (AR) signaling as well as non-canonical, AR-related mechanisms to modulate membrane receptor-mediated signal transduction, metabolic reprogramming, and the tumor immune microenvironment, thereby fostering tumor growth, metastasis, maintenance of stemness, and the development of therapy resistance. Notably, interventional strategies targeting testosterone/androgen signaling have entered clinical investigation and have demonstrated therapeutic promise. Beyond the best-developed clinical paradigms of prostate and breast cancer, we also highlight hepatocellular carcinoma and cutaneous melanoma as informative additional contexts that broaden the understanding of testosterone biology across cancers. Here, we propose that testosterone is best understood not simply as a hormonal input into isolated cancer pathways, but as a systems-level endocrine regulator of tumor plasticity that integrates transcriptional programs, rapid kinase signaling, and membrane receptor-associated responses across distinct tumor contexts. Within this framework, membrane androgen signaling is considered an emerging but still largely preclinical therapeutic vulnerability, whereas androgen-directed interventions in prostate and breast cancer represent the most clinically mature translational paradigms.
Zhou et al. (Wed,) studied this question.