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

Changfa Shu, Jianfeng Li, Jin Rui, Dacheng Fan, Qiankun Niu, Ruiyang Bai, Danielle Cicka, Sean Doyle, Alafate Wahafu, Xi Zheng, Yuhong Du, Andrey A. Ivanov, Deon B. Doxie, Kavita M. Dhodapkar, Jennifer Carlisle, Taofeek Owonikoko, Gabriel Sica, Yuan Liu, Suresh Ramalingam, Madhav. V Dhodapkar, Wei Zhou (), Xiulei Mo () and Haian Fu ()
Additional contact information
Changfa Shu: Emory University School of Medicine
Jianfeng Li: Emory University School of Medicine
Jin Rui: Emory University
Dacheng Fan: Emory University School of Medicine
Qiankun Niu: Emory University School of Medicine
Ruiyang Bai: Emory University School of Medicine
Danielle Cicka: Emory University School of Medicine
Sean Doyle: Emory University School of Medicine
Alafate Wahafu: Emory University School of Medicine
Xi Zheng: Emory University School of Medicine
Yuhong Du: Emory University School of Medicine
Andrey A. Ivanov: Emory University School of Medicine
Deon B. Doxie: Emory University
Kavita M. Dhodapkar: Winship Cancer Institute of Emory University
Jennifer Carlisle: Emory University
Taofeek Owonikoko: Emory University
Gabriel Sica: Winship Cancer Institute of Emory University
Yuan Liu: Winship Cancer Institute of Emory University
Suresh Ramalingam: Emory University
Madhav. V Dhodapkar: Emory University
Wei Zhou: Emory University
Xiulei Mo: Emory University School of Medicine
Haian Fu: Emory University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57297-5

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