The BCL-2 inhibitor APG-2575 resets tumor-associated macrophages toward the M1 phenotype,promoting a favorable response to anti-PD-1 therapy via NLRP3 activation  

作　　者：Fan Luo Han Li Wenjuan Ma Jiaxin Cao Qun Chen Feiteng Lu Miaozhen Qiu Penghui Zhou Zengfei Xia Kangmei Zeng Jianhua Zhan Ting Zhou Qiuyun Luo Wentao Pan Lin Zhang Chaozhuo Lin Yan Huang Li Zhang Dajun Yang Hongyun Zhao 

机构地区：[1]State Key Laboratory of Oncology in South China,Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy,Guangdong Provincial Clinical Research Center for Cancer,Sun Yat-sen University Cancer Center,Guangzhou,China [2]Ascentage Pharma(Suzhou)Co Ltd,218 Xinghu Street,Suzhou,Jiangsu Province,China

出　　处：《Cellular & Molecular Immunology》2024年第1期60-79,共20页中国免疫学杂志（英文版）

基　　金：supported by the Chinese National Natural Science Foundation Project(82073396,82303807);the Guangzhou Key Research and Development Plan(202206010141);the China National Postdoctoral Program for Innovative Talents(BX20230444);the China Postdoctoral Science Foundation(2023M734032).

摘　　要：The main challenges in the use of immune checkpoint inhibitors(ICIs)are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+T cells.Transforming the tumor microenvironment(TME)from“cold”to“hot”and thus more likely to potentiate the effects of ICIs is a promising strategy for cancer treatment.We found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+mouse models.Using single-cell RNA sequencing,we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion,restoring T-cell function and promoting a favorable immunotherapy response.Mechanistically,we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling,thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine production.As a result,APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment,thus improving tumor immunosuppression and further enhancing antitumor T-cell immunity.Multiplex immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86,p-NF-κB p65 and NLRP3 levels,accompanied by lower CD206 expression on macrophages.Collectively,these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.

关 键 词：BCL-2 APG-2575 ICIS MACROPHAGES NLRP3 

分 类 号：R392[医药卫生—免疫学]