Tyrosine kinase inhibitors (TKIs) have revolutionised the management of chronic myeloid leukaemia (CML), with the disease now having a five-year survival rate over 80%. The primary focus in the treatment of CML has been on improving the specificity and potency of TKIs to inhibit the activation of the BCR::ABL1 kinase and/or overcoming resistance driven by mutations in the BCR::ABL1 oncogene. However, this approach may be limited in a significant proportion of patients who develop TKI resistance despite the effective inhibition of BCR::ABL1. These patients may require novel therapeutic strategies that target both BCR::ABL1-dependent and BCR::ABL1-independent mechanisms of resistance. The combination treatment strategies that target alternative survival signalling, which may contribute towards BCR::ABL1-independent resistance, could be a successful strategy for eradicating residual leukaemic cells and consequently increasing the response rate in CML patients.

While there have been outstanding improvements in the treatment of Chronic Myeloid Leukaemia (CML), some patients do not respond optimally or are entirely resistant to treatment. In many of these patients, the molecular basis for resistance to tyrosine kinase inhibitors (TKIs) is unknown, highlighting the need for further investigation. Various potential mechanisms of TKI resistance are being explored with the aim of identifying new therapeutic options. A growing body of evidence suggests that alterations in lipid metabolism are implicated in treatment resistance in a variety of cancers including CML. Intracellular lipid storage may play a protective role to facilitate drug resistance in cancers and subsequently could serve as a targetable vulnerability. Due to the single genetic driver of oncogenesis, CML is an excellent model disease for studying metabolic alterations in cancer that contribute to drug resistance and disease progression. Based on the need to identify adjuvant therapies for TKI-resistant CML, we have evaluated evidence of dysregulated lipid storage in CML and its potential as a therapeutic target. In addition to in vitro analysis, we discuss the outcomes of clinical studies of CML treated with therapeutics that target lipid storage both directly and indirectly. We also highlight key limitations in the current literature and identify priority areas for further investigation. Advancing our understanding of lipid metabolic pathways, including lipid storage, in CML may reveal actionable vulnerabilities and support the development of novel therapeutic strategies to overcome TKI resistance.