2. Academic Validation
  3. Sonrotoclax (BGB-11417) synergistically amplifies the radiotherapy-elicited anti-tumor immune response

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

  • Cancer Lett. 2025 Aug 10:625:217759. doi: 10.1016/j.canlet.2025.217759.
Mengmeng Ma 1,  Zengfu Zhang 2,  Chen Tian 3,  Xu Liu 1,  Meng Wu 1,  Jinming Yu 4,  Jupeng Yuan 5,  Dawei Chen 6
Affiliations

Affiliations

  • 1 Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
  • 2 Department of Radiation Oncology, Shandong University Cancer Center, Jinan, Shandong, China.
  • 3 Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 4 Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China. Electronic address: sdyujinming@126.com.
  • 5 Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China. Electronic address: yuanjupeng1988@gmail.com.
  • 6 Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China; Department of Radiation Oncology, Shandong University Cancer Center, Jinan, Shandong, China. Electronic address: dave0505@yeah.net.
PMID: 40311913 DOI: 10.1016/j.canlet.2025.217759
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.

Keywords

BCL-2 inhibitor; Immunogenic ferroptosis; Macrophage; Radiotherapy; Sonrotoclax; cGAS-STING.

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