Neoliensinine promotes lysosomal cell death in T cell malignancies via a novel STING-TUBA1B pathway

The clinical treatment options for T cell malignancies (T-CMs) remain limited, and even the current popular immunotherapies have yet to demonstrate significant efficacy in addressing this disease. Identifying effective therapeutic targets for T-CMs and developing corresponding drugs are still critical goals in this field. Stimulator of interferon genes (STING) is highly expressed in T cells and plays a pivotal role in T cell immunity. However, the mechanisms underlying STING-mediated cell death are not well understood. Neoliensinine (NeoL), a unique bisbenzylisoquinoline alkaloid from Nelumbo nucifera Gaertn, has been shown to be promising as a cytotoxic agent in this context. Here, we investigated NeoL and uncovered a novel mechanism linking STING-induced lysosome-dependent cell death in T-CMs. NeoL was found to bind to and activate STING, promoting its trafficking to lysosomes for degradation. This process was coordinated by tubulin alpha 1b (TUBA1B), a key microtubule isoform. The trafficking of STING to lysosomes disrupted cholesterol homeostasis, leading to lysosomal cholesterol accumulation. This, in turn, triggered lysosomal dysfunction, including lysosomal damage, membrane permeabilization, and cell death. Blocking any part of the STING-TUBA1B-lysosomal cholesterol accumulation axis attenuated NeoL-induced lysosomal disorders and T-CM cell death without significant effect on normal peripheral blood mononuclear cells. NeoL also decreased the growth of T-CM-derived tumors in vivo. These findings suggest that targeting STING-TUBA1B in T-CMs with NeoL is a promising therapeutic approach and provide a potential agent for improving T-CM therapy.