Abstract Eukaryotic cells preserve proteostasis and organelle integrity through two interconnected degradation machineries: the ubiquitin-proteasome system (UPS) and autophagy. Together, these pathways constitute a coordinated quality control network that orchestrates the selective turnover of misfolded proteins and damaged organelles. Proteasome inhibitors have achieved clinical success in hematologic malignancies, but their activity is limited by intrinsic and acquired resistance, which varies substantially across cancer types. In this study, we hypothesize that autophagy inhibition can overcome resistance to proteasome inhibition. Mechanistically, proteasome inhibition induces endoplasmic reticulum (ER) stress in sensitive cancer cells but fails to elicit this response in resistant ones. Co-treatment with autophagy inhibitors restore ER stress induction and synergistically enhances cytotoxicity in the resistant cells. In multiple in vivo cancer models including pancreatic and triple-negative breast cancers, combined inhibition of autophagy and UPS synergistically inhibited tumor growth and improved survival outcomes. At the molecular level, this dual blockade activates the PERK-pEIF2α-ATF4 signaling axis effectively, leading to apoptotic cell death. Collectively, our findings identify a mechanistic basis for overcoming resistance to proteasome inhibitors and provide a rationale for future clinical evaluation of autophagy-UPS combinatorial therapy across diverse malignancies. Citation Format: Jing Li, Yi Bao, Ava Cardenas, Ariba Saoda, Fengyu Su, Yuanyuan Qiao, Xuhong Cao, Arul M. Chinnaiyan. Targeting autophagy sensitizes cancer cells to proteasome inhibitors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1272.
Li et al. (Fri,) studied this question.