CDK12/13 inhibition induces immunogenic cell death and enhances anti-PD-1 anticancer activity in breast cancer.

Immunogenic cell death (ICD) improves the T cell response against different tumors, indicating that ICD can enhance the antitumor immunity elicited by the anti-checkpoint antibody anti-programmed death 1 (anti-PD-1). In the present study, we reported a synergistic and durable immune-mediated antitumor response elicited by the combined treatment of SR-4835, a CDK12/13 specific inhibitor, with PD-1 blockade in a syngeneic mouse model. The developed combination therapy elicited antitumor activity in immunocompetent mouse tumor models. Furthermore, the SR-4835-treated tumor cells exhibited characteristics of ICD, including the release of high mobility group box 1 (HMGB1) and ATP and calreticulin (CRT) translocation. This activity led to a significant T-cell-dependent tumor suppression. The enhanced dendritic cell (DC) and infiltration of T cells activation in the tumors treated with both SR-4835 and anti-PD-1 indicate that this combination treatment promotes an improved immune response. Therefore, the results of the present study demonstrate the potential of CDK12/13 inhibition combined with checkpoint inhibition in breast cancer treatment.