Antiemesis Corticosteroids Potentiate Checkpoint Blockade Efficacy by Normalizing the Immune Microenvironment in Metastatic Murine Breast Cancer

Corticosteroids improve the efficacy of immune checkpoint blockade therapy in metastatic murine breast cancer. By normalizing the tumor immune microenvironment, corticosteroids reduce immunosuppressive signals, restore T‐cell function, and promote antitumor immune responses, resulting in enhanced tumor control. Abstract Glucocorticoid steroids are widely prescribed in oncology for managing treatment‐related side effects, though their use is discouraged in patients undergoing immune checkpoint blockade (ICB). Given the crucial role of steroids in supportive care, it is imperative to develop integrated strategies that do not compromise ICB therapy effectiveness. Here, protocols of dexamethasone resembling clinical antiemesis regimens are tested in murine models of ICB‐resistant breast cancer. Unexpectedly, dexamethasone enhanced the efficacy of ICB in models of primary cancer and spontaneous metastasis. Dexamethasone increased the volume of blood vessels within tumors, thereby facilitating lymphocyte infiltration and intratumor distribution. Additionally, dexamethasone depleted immunosuppressive cells and potentiated the capacity of ICB to enrich tumors of antigen‐recognizing cytotoxic lymphocytes. Importantly, it is found that dexamethasone does not abolish the functions of antigen‐naïve lymphocytes and has no effect on the activity of antigen‐experienced lymphocytes. These findings align with recent clinical guidelines and meta‐analyses, suggesting that dexamethasone deserves further exploration in ICB protocols to potentially benefit efficacy. Our study supports the notion that the current practice of avoiding short‐term glucocorticoid steroids in patients receiving ICB should be reconsidered toward enabling the use of steroids in clinical trials of new drug combinations. Corticosteroids improve the efficacy of immune checkpoint blockade therapy in metastatic murine breast cancer. By normalizing the tumor immune microenvironment, corticosteroids reduce immunosuppressive signals, restore T-cell function, and promote antitumor immune responses, resulting in enhanced tumor control. Abstract Glucocorticoid steroids are widely prescribed in oncology for managing treatment-related side effects, though their use is discouraged in patients undergoing immune checkpoint blockade (ICB). Given the crucial role of steroids in supportive care, it is imperative to develop integrated strategies that do not compromise ICB therapy effectiveness. Here, protocols of dexamethasone resembling clinical antiemesis regimens are tested in murine models of ICB-resistant breast cancer. Unexpectedly, dexamethasone enhanced the efficacy of ICB in models of primary cancer and spontaneous metastasis. Dexamethasone increased the volume of blood vessels within tumors, thereby facilitating lymphocyte infiltration and intratumor distribution. Additionally, dexamethasone depleted immunosuppressive cells and potentiated the capacity of ICB to enrich tumors of antigen-recognizing cytotoxic lymphocytes. Importantly, it is found that dexamethasone does not abolish the functions of antigen-naïve lymphocytes and has no effect on the activity of antigen-experienced lymphocytes. These findings align with recent clinical guidelines and meta-analyses, suggesting that dexamethasone deserves further exploration in ICB protocols to potentially benefit efficacy. Our study supports the notion that the current practice of avoiding short-term glucocorticoid steroids in patients receiving ICB should be reconsidered toward enabling the use of steroids in clinical trials of new drug combinations. Advanced Science, EarlyView.