Modeling the MRD state reveals the insomnia of chemotherapy-tolerant persister clones

Regardless of the success of clinical surgery, disseminated tumor cells (DTCs) can persist in distant organs, with a fraction surviving chemotherapy, which can result in minimal residual disease (MRD), a relevant reservoir for metastatic relapse. Yet, the cellular states that enable the survival and outgrowth of MRD remain poorly defined. Here, using a patient-derived tongue cancer organoid (TCO) model, we recapitulated the key features of chemotherapy-tolerant DTCs by culturing TCOs under growth-factor deprivation and chemotherapeutic stress conditions that mimic the metastatic tissue environment. Clonal-level analyses revealed a distinct subset of cells that retained proliferative capacity without entering a therapy-induced cytostatic state (hereafter referred to as cycling persisters, CPs). CPs exhibited coordinated activation of the IFN signaling pathway, Xenobiotic metabolism, and inflammatory signaling pathways, defining a transcriptional and metabolic program that enables sustained proliferation of CPs under the poor conditions. Consistently, a cell population with similar features was identified in metastatic tissues from patients. Longitudinal clonal tracking demonstrated that early metastatic recurrence is more likely driven by CPs, suggesting a novel mechanism that differs from the prevailing view that relapse arises from reactivation of dormant non-CPs. Our findings highlight a critical therapeutic oversight in relapse prevention.