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 LKB1-IAP-JAK 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-established JAK-regulated STING expression and DNA sensing signaling, enhanced cytotoxic immune cell infiltration, and augmented immune-dependent anti-tumor activity in an LKB1-mutant immune-competent mouse model. Thus, IAP-JAK-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.