Revisiting prophylactic corticosteroids to mitigate severe immune-related adverse events in hepatocellular carcinoma

Dual immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) or its ligand (PD-L1) have reshaped the treatment landscape of unresectable hepatocellular carcinoma (HCC). However, their clinical uptake remains limited by the high incidence of severe immune-related adverse events (irAEs), underscoring the urgent need for effective prophylactic strategies. Corticosteroids are traditionally viewed as antagonistic to antitumour immunity and have long been prohibited from prophylactic use in ICI-only regimens. Yet this dogma is increasingly at odds with both clinical practice and emerging evidence. Prophylactic corticosteroids (PC) are routinely administered in patients with lung cancer receiving immunochemotherapy, primarily to prevent chemotherapy-related toxicity. In this context, prophylactic corticosteroids have been associated with a reduction in severe irAEs without compromising efficacy. Our preclinical HCC studies demonstrate that corticosteroid premedication does not impair T-cell activation or antitumour activity induced by dual ICI therapy. Emerging clinical data similarly suggest that baseline or concomitant corticosteroid use does not adversely affect oncological outcomes in HCC. In this Expert Opinion, we argue that it is time to rethink the long-standing prohibition of prophylactic corticosteroids in ICI-based treatment. Judicious prophylactic corticosteroid use may offer a practical means to mitigate severe irAEs - particularly in anti-CTLA-4-containing regimens - while maintaining antitumour activity. We advocate for prospective evaluation of prophylactic corticosteroids in ICI-based regimens associated with higher immune-mediated toxicity, to better define their role in HCC.