Compartmentalisation of death receptor signalling in cancer

Death Receptor (DR) ligands, such as CD95L and TRAIL, are historically considered as key players of tumour immunosurveillance through their ability to induce cell death. Yet, depending on the cellular context, their corresponding DR, CD95 and TRAILR1/2, also initiate various non-cytotoxic pathways and cellular functions and display multiple pro-tumoural functions across various cancer types. To unleash the full potential of the therapeutic targeting of DR signalling, it is therefore essential to understand the molecular mechanisms that tip the scales between their anti- and pro-tumoural effects. DR signalling is physiologically tightly regulated, and hence widely dysregulated in cancer, at multiple steps. Herein, focusing on the DR CD95, TRAILR1/2 and TNFR1, we first summarise their main signalling regulatory steps and therapeutic strategies developed for their targeting in cancer. Then, we focus on the emerging and sometimes controversial roles of cellular compartmentalisation in the regulation of DR signalling in cancer.