Uncovering the rewired IAP-JAK regulatory axis as an immune-dependent vulnerability of LKB1-mutant lung cancer
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.
Authors
- Sean P. Doyle (ORCID: https://orcid.org/0000-0002-2774-2763)
- Jennifer W. Carlisle (ORCID: https://orcid.org/0000-0001-7085-4640)
- Danielle Cicka (ORCID: https://orcid.org/0000-0002-9630-2489)
- Taofeek K. Owonikoko (ORCID: https://orcid.org/0000-0002-7724-7728)
- Yuan Liu (ORCID: https://orcid.org/0000-0001-8926-3058)
- Gabriel Sica
- Changfa Shu (ORCID: https://orcid.org/0000-0002-6216-5623)
- Xiulei Mo
- Dacheng Fan (ORCID: https://orcid.org/0000-0001-9426-2543)
- Deon B. Doxie (ORCID: https://orcid.org/0000-0002-5383-0441)
- Andrei A. Ivanov (ORCID: https://orcid.org/0000-0001-7476-1329)
- Wei Zhou (ORCID: https://orcid.org/0000-0002-6783-9957)
- Alafate Wahafu (ORCID: https://orcid.org/0000-0002-4791-1966)
- Haian Fu (ORCID: https://orcid.org/0000-0002-2362-7979)
- Kavita M. Dhodapkar (ORCID: https://orcid.org/0000-0003-0587-4172)
- Suresh S. Ramalingam (ORCID: https://orcid.org/0000-0002-0757-3106)
- Madhav V. Dhodapkar (ORCID: https://orcid.org/0000-0002-8249-5988)
- Rui Jin (ORCID: https://orcid.org/0000-0001-5456-2381)
- Qiankun Niu (ORCID: https://orcid.org/0000-0003-1781-5436)
- Jianfeng Li (ORCID: https://orcid.org/0000-0002-3168-7832)
- Ruiyang Bai
- Xi Zheng
- Yuhong Du
Institutions
- Emory Healthcare (US)
- Central South University (CN)
- Emory University (US)
- Zhejiang Cancer Hospital (CN)
- Aflac (United States) (US)
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- Children's Healthcare of Atlanta (US)
- Third Xiangya Hospital (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Xiangya Hospital Central South University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-08
- DOI
- https://doi.org/10.1038/s41467-025-57297-5
- Citations
- 3
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 2.39
Funders
- National Cancer Institute