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Proteasome inhibitors significantly improve cancer outcomes, but their use is eventually followed by proteasome inhibitor resistance and relapse. Current understanding of proteasome inhibitor resistance is limited to cell‐autonomous mechanisms; whether non–autonomous mechanisms can be implicated in the development of proteasome inhibitor resistance is unclear. Here, we show that proteasome inhibitor tolerance can be transmitted non–autonomously through exosome‐mediated intercellular interactions. We revealed that reversible proteasome inhibitor resistance can be transmitted from cells under therapy stress to naïve sensitive cells through exosome‐mediated cell cycle arrest and enhanced stemness in mixed‐lineage leukemia cells. Integrated multi‐omics analysis using the Tied Diffusion through Interacting Events algorithm identified several candidate exosomal proteins that may serve as predictors for proteasome inhibitor resistance and potential therapeutic targets for treating refractory mixed‐lineage leukemia. Furthermore, inhibiting the secretion of exosomes is a promising strategy for reversing proteasome inhibitor resistance in vivo, which provides a novel proof of principle for the treatment of other refractory or relapsed cancers.

Exosomes mediate intercellular transfer of non–autonomous tolerance to proteasome inhibitors in mixed‐lineage leukemia