γδ T cells are a unique subset of T lymphocytes, exhibiting features of both innate and adaptive immune cells and are involved with cancer immunosurveillance. They present an attractive alternative to conventional T cell‐based immunotherapy due, in large part, to their lack of major histocompatibility (MHC) restriction and ability to secrete high levels of cytokines with well‐known anti‐tumour functions. To date, clinical trials using γδ T cell‐based immunotherapy for a range of haematological and solid cancers have yielded limited success compared with in vitro studies. This inability to translate the efficacy of γδ T‐cell therapies from preclinical to clinical trials is attributed to a combination of several factors, e.g. γδ T‐cell agonists that are commonly used to stimulate populations of these cells have limited cellular uptake yet rely on intracellular mechanisms; administered γδ T cells display low levels of tumour‐infiltration; and there is a gap in the understanding of γδ T‐cell inhibitory receptors. This review explores the discrepancy between γδ T‐cell clinical and preclinical performance and offers viable avenues to overcome these obstacles. Using more direct γδ T‐cell agonists, encapsulating these agonists into lipid nanocarriers to improve their pharmacokinetic and pharmacodynamic profiles and the use of combination therapies to overcome checkpoint inhibition and T‐cell exhaustion are ways to bridge the gap between preclinical and clinical success. Given the ability to overcome these limitations, the development of a more targeted γδ T‐cell agonist‐checkpoint blockade combination therapy has the potential for success in clinical trials which has to date remained elusive.

Multiple myeloma (MM) is an incurable malignancy of plasma cells that accounts for 10% of all haematological malignancies diagnosed worldwide. The poor outcome of patients with MM highlights the ongoing need for novel treatment strategies. Ferroptosis is a recently characterised form of non-apoptotic programmed cell death. Phospholipids (PLs) containing polyunsaturated fatty acids (PUFAs) play a crucial role as ferroptosis substrates when oxidised to form toxic lipid reactive oxygen species (ROS). Using a range of scientific techniques, we demonstrate a strong correlation between the PL profile of MM and diffuse large B cell lymphoma (DLBCL) cells with their sensitivity to ferroptosis. Using this PL profiling, we manufacture liposomes that are themselves composed of PL-PUFA ferroptosis substrates relatively deficient in MM cells, with and without the GPX4 inhibitor, RSL3, for investigation of their ferroptosis-inducing potential. PL-PUFAs were more abundant in DLBCL than MM cell lines, consistent with greater ferroptosis sensitivity. In contrast, MM cells generally contained a significantly higher proportion of PLs containing monounsaturated fatty acids. Altering the lipid composition of MM cells through exogenous supplementation with PL-PUFAs induced ferroptosis-mediated cell death and further sensitised these cells to RSL3. Liposomes predominantly comprising PL-PUFAs were subsequently manufactured and loaded with RSL3. Uptake, cytotoxicity and lipid ROS studies demonstrated that these novel liposomes were readily taken up by MM cells. Those containing RSL3 were more effective at inducing ferroptosis than empty liposomes or free RSL3, resulting in IC₅₀ values an average 7.1-fold to 14.5-fold lower than those for free RSL3, from the micromolar to nanomolar range. We provide a better understanding of the mechanisms associated with ferroptosis resistance of MM cells and suggest that strategies such as liposomal delivery of relatively deficient ferroptosis-inducing PL-PUFAs together with other targeted agents could harness ferroptosis for the personalised treatment of MM and other cancers.