Entering a drug‐tolerant persister (DTP) state of cancer cells is a transient self‐adaptive mechanism by which a residual cell subpopulation accelerates tumor progression. Here, we identified the acquisition of a DTP phenotype in multidrug‐resistant (MDR) cancer cells as a tolerance response to routine combination treatment. Characterization of MDR cancer cells with a DTP state by RNA‐seq revealed that these cells partially prevented chemotherapy‐triggered oxidative stress by promoting NPC1L1‐regulated uptake of vitamin E. Treatment with the NPC1L1 inhibitor ezetimibe further enhanced the therapeutic effect of combinatorial therapy by inducing methuosis. Mechanistically, we demonstrated that NRF2 was involved in transcriptional regulation of NPC1L1 by binding to the −205 to −215 bp site on its promoter. Decreased DNA methylation was also related partially to this process. Furthermore, we confirmed that a triple‐combination of chemotherapeutic agents, verapamil, and ezetimibe, had a significant anti‐tumor effect and prevented tumor recurrence in mice. Together, our study provides a novel insight into the role of DTP state and emphasizes the importance of disrupting redox homeostasis during cancer therapy.

Antioxidants play a pivotal role in neutralizing reactive oxygen species (ROS), which are known to induce oxidative stress. In the context of cancer development, cancer cells adeptly maintain elevated levels of both ROS and antioxidants through a process termed “redox reprogramming”. This balance optimizes the proliferative influence of ROS while simultaneously reducing the potential for ROS to cause damage to the cell. In some cases, the adapted antioxidant machinery can hamper the efficacy of treatments for neoplastic diseases, representing a significant facet of the resistance mechanisms observed in cancer therapy. In this review, we outline the contribution of antioxidant systems to therapeutic resistance. We detail the fundamental constituents of these systems, encompassing the central regulatory mechanisms involving transcription factors (of particular importance is the KEAP1/NRF2 signaling axis), the molecular effectors of antioxidants, and the auxiliary systems responsible for NADPH generation. Furthermore, we present recent clinical trials based on targeted antioxidant systems for the treatment of cancer, assessing the potential as well as challenges of this strategy in cancer therapy. Additionally, we summarize the pressing issues in the field, with the aim of illuminating a path toward the emergence of novel anticancer therapeutic approaches by orchestrating redox signaling.

Pancreatic cancer (PC) continues to demand urgent therapeutic innovation given its limited treatment options. Here, through phenotypic screening of a natural product library followed by systematic validation, we identified chrysosplenetin (CHR) as a bioactive compound with anti-PC activity. Transcriptomic profiling and functional analyses demonstrated that CHR induced endoplasmic reticulum (ER) stress, thereby activating the unfolded protein response (UPR) and subsequent apoptosis, while paradoxically triggering a protective autophagy. Genetic or pharmacological inhibition of autophagy potentiated CHR-induced antitumor efficacy. Using an integrated approach including proteomic analysis, bio-layer interferometry, cellular thermal shift assay, and molecular docking, we confirmed TMED3 as a direct target of CHR. Functional studies revealed that disruption of TMED3 expression partially restored ER homeostasis, attenuating CHR-induced UPR activation and apoptosis. Furthermore, CHR combined with standard chemotherapy or autophagy inhibitors exhibited enhanced antitumor activity in preclinical models, providing a basis for future therapeutic exploration of the TMED3–ER stress axis. Together, our findings establish TMED3 as a novel therapeutic target in PC, revealing that disrupting ER proteostasis via TMED3 perturbation represents a potential therapeutic strategy warranting further investigation.