Sonrotoclax (BGB-11417) synergistically amplifies the radiotherapy-elicited anti-tumor immune response

Abstract

Escape from apoptosis is one of the main hallmarks of cancer. The imbalance of BCL-2 family members is a key factor leading to radiotherapy resistance. Targeting BCL-2 can overcome radiotherapy resistance by promoting apoptosis. Nevertheless, the function of BCL-2 in regulating the tumor immune microenvironment (TIME) is still not well understood. Herein, we discovered that the specific BCL-2 inhibitor sonrotoclax (BGB-11417) boosted the effectiveness of radiotherapy in an immune-mediated manner. Using flow cytometry, we found that sonrotoclax combined with radiotherapy polarized tumor-associated macrophages (TAMs) toward the M1-type and promoted the infiltration of Gzmb⁺ CD8⁺ T cells into the tumor. Mechanistically, we demonstrated that the combination of sonrotoclax and radiotherapy induced immunogenic ferroptosis of cancer cells by inhibiting GPX4 expression, released tumor-associated damage-associated molecular patterns (DAMPs) and subsequently activated the NF-κB pathway in TAMs. Moreover, the combination therapy also led to aberrant cytosolic DNA abundance and activated the cGAS-STING pathway in cancer cells, leading to the release of type I interferons and enhanced activation of CD8⁺ T cells. Meanwhile, the activation of cGAS-STING pathway also led to the upregulation of PD-L1 expression. Further combination of sonrotoclax and radiotherapy plus anti-PD-L1 exerted the most significant anti-tumor effects. Overall, our study indicated that sonrotoclax enhanced the anti-tumor immune response of radiotherapy through non-apoptotic roles of BCL-2, and shed light on the further clinical evaluation of the triple combination therapy of sonrotoclax, radiotherapy and immunotherapy.