Uncovering the rewired IAP-JAK regulatory axis as an immune-dependent vulnerability of LKB1-mutant lung cancer

Nat Commun. 2025 Mar 8;16(1):2324. doi: 10.1038/s41467-025-57297-5.

Changfa Shu ¹ ², Jianfeng Li ¹, Jin Rui ³, Dacheng Fan ¹, Qiankun Niu ¹, Ruiyang Bai ¹ ⁴, Danielle Cicka ¹, Sean Doyle ¹, Alafate Wahafu ¹ ⁵, Xi Zheng ¹ ⁶, Yuhong Du ¹ ⁷ ⁸, Andrey A Ivanov ¹ ⁷ ⁸, Deon B Doxie ³, Kavita M Dhodapkar ⁸ ⁹, Jennifer Carlisle ³ ⁸, Taofeek Owonikoko ³ ⁸, Gabriel Sica ⁸ ¹⁰, Yuan Liu ⁸ ¹¹, Suresh Ramalingam ³ ⁸, Madhav V Dhodapkar ³ ⁸, Wei Zhou ¹² ¹³, Xiulei Mo ¹⁴ ¹⁵, Haian Fu ¹⁶ ¹⁷ ¹⁸ ¹⁹

Affiliations

1 Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA.
2 Department of Obstetrics and Gynecology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, P R China.
3 Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA.
4 Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
5 The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shannxi, P R China.
6 Cancer Institute, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P R China.
7 Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, USA.
8 Winship Cancer Institute of Emory University, Atlanta, GA, USA.
9 Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA, USA.
10 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
11 Rollins School of Public Health, Emory University, Atlanta, GA, USA.
12 Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA. wzhou2@emory.edu.
13 Winship Cancer Institute of Emory University, Atlanta, GA, USA. wzhou2@emory.edu.
14 Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA. xmo@emory.edu.
15 Winship Cancer Institute of Emory University, Atlanta, GA, USA. xmo@emory.edu.
16 Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA. hfu@emory.edu.
17 Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA. hfu@emory.edu.
18 Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, USA. hfu@emory.edu.
19 Winship Cancer Institute of Emory University, Atlanta, GA, USA. hfu@emory.edu.

PMID: 40057483 DOI: 10.1038/s41467-025-57297-5

Abstract

Harnessing the power of immune system to treat Cancer has become a core clinical approach. However, rewiring of intrinsic circuitry by genomic alterations enables tumor cells to escape immune surveillance, leading to therapeutic failure. Uncovering the molecular basis of how tumor mutations induce therapeutic resistance may guide the development of intervention approaches to advance precision immunotherapy. Here we report the identification of the Liver Kinase B1 (LKB1)-Inhibitor of Apoptosis Protein (IAP)- Janus Kinase 1 (JAK1) dynamic complex as a molecular determinant for immune response of LKB1-mut lung Cancer cells. LKB1 alteration exposes a critical dependency of lung Cancer cells on IAP for their immune resistance. Indeed, pharmacological inhibition of IAP re-establishes JAK1-regulated Stimulator of interferon genes (STING) expression and DNA sensing signaling, enhances cytotoxic immune cell infiltration, and augmentes immune-dependent anti-tumor activity in an LKB1-mutant immune-competent mouse model. Thus, IAP-JAK1-targeted strategies, like IAP inhibitors, may offer a promising therapeutic approach to restore the responsiveness of immunologically-cold LKB1-mutant tumors to Immune Checkpoint inhibitors or STING-directed therapies.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-16591

Birinapant

99.70%, XIAP/cIAP1 Antagonist

IAP; Apoptosis; HIV

Cancer

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