Beyond mitotane: next-generation therapeutic landscapes in adrenocortical carcinoma.

Abstract The clinical management of adrenocortical carcinoma (ACC) has long been defined by its resistance to conventional therapies. Since the FIRM-ACT trial established the combination of etoposide, doxorubicin, and cisplatin plus mitotane (EDP-M) as the frontline standard, overall survival for metastatic patients has remained stubbornly low. This plateau in efficacy with cytotoxic regimes has necessitated a shift toward precision oncology and immunotherapy. However, translating the success of immune-checkpoint inhibitors seen in other malignancies to ACC has proven exceptionally difficult. The primary challenge in the present therapeutic landscape of immunotherapy is the unique biology of the adrenal cortex, which creates an intrinsic immunologically privileged site. This review will address these current immunological hurdles but also explore novel strategies designed to bypass this barrier entirely. By shifting focus toward mechanisms that do not solely rely on the traditional engagement of adaptive immune system—such as the targeted delivery of cytotoxic payloads via antibody-drug conjugates (ADCs) or the androgen-mediated activation of myeloid cells to clear pro-tumoral populations —the field is moving toward a future where the "cold" nature of the tumour microenvironment may no longer dictate the limits of therapeutic success.