Interleukin-1 receptor-associated kinase 1 controls chemoresistance and immuno-killing in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) shows partial chemoimmunoresistance, driven by the upregulation of the drug efflux transporters ABCB1 and ABCC1 and the downregulation of the immunosensitizer protein ABCA1. To elucidate the molecular mechanisms underlying this chemoimmunoresistant phenotype, by performing a CRISPR-KO kinome screening, we identified interleukin-1 receptor-associated kinase 1 (IRAK1) as a key determinant of chemoimmunosensitive and chemoimmunoresistant phenotypes, defined as ABCB1/ABCC1lowABCA1high and ABCB1/ABCC1highABCA1low, respectively. IRAK1 expression was significantly associated with poor prognosis in the TCGA-LUAD cohort and in early-stage NSCLC patients. The IRAK1/ABCB1/ABCC1highABCA1low signature was predictive of poor response to chemotherapy and immunotherapy in advanced-stage patients. Mechanistically, IRAK1 silencing resensitized NSCLC cells to cisplatin by decreasing IL-1R/NFκB and IL-1R/AP-1 signaling, which in turn downregulated the drug efflux transporters ABCB1 and ABCC1. Concurrently, IRAK1 silencing activated the LXRα/ABCA1 axis, which enhanced Vγ9Vδ2 Tcell-mediated cytotoxicity and facilitated the recruitment of memory and effector CD4+ and CD8+ T cells in both ex vivo autologous cocultures and immunoxenografts, increasing the immuno-killing ability of tumor cells. Newly developed synthetic inhibitors of IRAK1 efficiently promoted chemo- and immunosensitization in immunoxenografts, resulting in good pharmacokinetic and safety profiles. These findings identify IRAK1 as a novel, druggable target that controls both chemoresistance and immune evasion in NSCLC. We suggest the pharmacological inhibition of IRAK1 as a future promising strategy to overcome resistance to chemotherapy and improve patient outcomes.