Chemotherapy’s Hidden Survivors: Lactylation Switch Reveals How Colorectal Cancer Cells Hide From Treatment

Colorectal cancer remains one of the deadliest malignancies worldwide, and even the most aggressive chemotherapy regimens can fail in a frustratingly subtle way. Tumors often shrink in response to treatment, yet a small population of cells survives in a quiet, altered state, only to seed regrowth weeks or months later. A new study published in Molecular Cancer has now uncovered a remarkably detailed molecular mechanism that allows these so-called drug-tolerant persister cells to endure the onslaught of FOLFOXIRI, an intensive combination regimen of 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan. The research reveals that a single chemical modification on a single mitochondrial protein acts as a master switch, rewiring cancer cell metabolism and permitting survival under conditions that should be lethal.

The research team, led by investigators at Shandong University and collaborating institutions across China, set out to answer a question that has puzzled oncologists for years: how do colorectal cancer cells that survive chemotherapy manage to keep their mitochondria, the cellular power plants, in working order? Drug-tolerant persister cells are known to enter a reversible adaptive state, rather than acquiring permanent genetic resistance mutations, which makes them especially insidious. When therapy stops, these cells can resume proliferation and regenerate the tumor with its original drug sensitivity intact. The researchers built a comprehensive experimental system to catch these cells in the act, using patient-derived xenografts, organoids grown from patient tumors, conventional colorectal cancer cell lines, and cell line-derived xenografts in animal models.

What they observed in the surviving cells was a profound metabolic transformation. The persister cells showed markedly reduced proliferation without a corresponding increase in apoptosis, the programmed cell death that chemotherapy is designed to trigger. When the researchers withdrew the drugs, the cells resumed growth, confirming that the tolerant state was genuinely reversible. At the metabolic level, the persister cells suppressed glycolysis, the sugar-burning pathway that most cancer cells rely on heavily, and produced far less lactate, the acidic byproduct of that pathway. Instead, they became increasingly dependent on oxidative phosphorylation, the more efficient mitochondrial process that generates cellular energy using oxygen. This metabolic shift was accompanied by a striking activation of mitophagy, the cellular quality-control system that selectively recycles damaged mitochondria.

The centerpiece of the discovery is a protein called UQCRC2, or ubiquinol-cytochrome c reductase core protein 2, a structural component of complex III in the mitochondrial electron transport chain. The researchers found that UQCRC2 accumulated in the drug-tolerant persister cells, where it supported Parkin and SQSTM1-associated mitophagy and enabled the residual cells to survive. But the truly novel element lies in how UQCRC2 is regulated. The team employed an emerging field of post-translational modification research known as lactylomics, using global mass-spectrometry-based profiling to map lysine lactylation sites, a chemical tagging process in which lactate-derived lactyl groups attach to lysine residues on proteins. Because the persister cells produced less lactate, the overall level of lysine lactylation across the proteome dropped, and specifically, lactylation of UQCRC2 at the amino acid lysine 430 declined sharply.

Here the story takes a turn worthy of a molecular thriller. When UQCRC2 is heavily lactylated at position 430, the modified protein becomes a target for K48-linked ubiquitination, a molecular tag that condemns proteins to destruction by the proteasome, the cell’s waste-disposal machinery. Reduced lactylation therefore protects UQCRC2 from degradation and allows it to accumulate. The researchers identified the enzyme responsible for removing the lactyl tag: SIRT1, a member of the sirtuin family of NAD-dependent deacylases that has long been associated with longevity, stress resistance, and metabolic regulation. Through a cell-free delactylation assay, the team demonstrated that SIRT1 directly removes the lactylation from UQCRC2 at lysine 430 in a manner dependent on NAD, the cellular energy carrier. This delactylation stabilizes UQCRC2, preserving mitochondrial function and fueling the mitophagy program that keeps the persister cells alive.

The functional consequences of this pathway were confirmed through a series of genetic and pharmacological experiments. When the researchers depleted PINK1, the kinase that initiates the mitophagy cascade, or knocked down UQCRC2 itself, the survival of the residual drug-tolerant cells plummeted and tumor regrowth was significantly delayed. Inhibiting SIRT1, either genetically or with drugs, produced the same effect, effectively collapsing the survival mechanism that the persister cells depend upon. These results suggest that the SIRT1-UQCRC2 axis represents a genuine therapeutic vulnerability, a chink in the armor of chemotherapy-tolerant cells that could be exploited to prevent the outgrowth of tumors after treatment.

Perhaps the most clinically significant finding came from analyses of actual patient samples. Among chemotherapy-responsive patients with advanced colorectal cancer, low expression of the UQCRC2-K430 lactylation mark in tumor tissue remained associated with poorer overall survival even after multivariable statistical adjustment. The researchers also examined paired samples of circulating tumor cells, rare cancer cells that travel through the bloodstream, collected from patients before and after chemotherapy exposure. In these paired samples, increased SIRT1 expression or decreased UQCRC2-K430 lactylation after chemotherapy was associated with shorter progression-free survival. This pattern suggests that the molecular signature of the persister state, detectable in a simple blood-based assay, could serve as an early warning system identifying patients whose residual disease is primed for relapse.

The methodological breadth of the study deserves particular attention. By integrating whole-exome sequencing with transcriptomic, proteomic, metabolomic, and lactylomic analyses, the researchers were able to triangulate the mechanism from multiple independent angles, ruling out genetic mutation as the driver and instead pointing to a reversible epiproteomic program. Whole-exome sequencing confirmed that the persister cells had not acquired new resistance mutations, while the multi-omic profiling revealed the coordinated metabolic and post-translational remodeling that defines the tolerant state. Metabolic assays measuring oxygen consumption and extracellular acidification rates quantified the shift from glycolysis to oxidative phosphorylation, while protein stability and ubiquitination analyses traced the fate of UQCRC2 through the degradation pathway.

The broader implications of this work extend well beyond colorectal cancer. Drug-tolerant persister cells have been implicated in treatment failure across many tumor types, and the discovery that lysine lactylation functions as a metabolic sensor linking glycolytic output to mitochondrial quality control provides a unifying framework for understanding how cancer cells weather therapeutic stress. Lactate, long dismissed as a mere metabolic waste product, is increasingly recognized as a signaling molecule, and this study adds a striking new dimension to that picture: lactate levels directly tune the stability of a core respiratory protein, thereby determining whether a cell can maintain the mitochondrial infrastructure needed to survive chemotherapy. The finding also positions sirtuins, and SIRT1 in particular, as enzymatic gatekeepers of this lactylation-dependent survival program, raising the prospect that existing and experimental SIRT1 inhibitors could be repurposed as anti-persister agents.

For patients, the road from laboratory discovery to clinical application is long, but this study offers concrete waypoints. The identification of UQCRC2-K430 lactylation as a candidate biomarker of chemotherapy-associated residual disease opens the door to trials that could monitor this mark in circulating tumor cells during treatment, potentially allowing oncologists to intervene before overt relapse occurs. Therapeutic strategies that combine standard FOLFOXIRI chemotherapy with agents that disrupt the SIRT1-UQCRC2-mitophagy axis could, in principle, eliminate the reservoir of persister cells that currently seed tumor regrowth. As the authors conclude, this low-lactate, SIRT1-regulated mechanism couples metabolic suppression to mitochondrial quality control and enables reversible chemotherapy tolerance, and it now stands as one of the most mechanistically complete portraits of drug tolerance assembled in any cancer type to date. The study was supported by the National Natural Science Foundation of China and multiple Chinese research foundations, and the full open-access article is available in Molecular Cancer.

Subject of Research: Lactylation-mediated mitophagy in colorectal cancer drug tolerance during chemotherapy

Article Title: UQCRC2 lactylation-mediated mitophagy orchestrates colorectal cancer cell metabolism to establish a drug-tolerant state during chemotherapy

Article References: UQCRC2 lactylation-mediated mitophagy orchestrates colorectal cancer cell metabolism to establish a drug-tolerant state during chemotherapy. (n.d.). https://doi.org/10.1186/s12943-026-02793-5

Image Credits: AI Generated

DOI: 10.1186/s12943-026-02793-5

Keywords: colorectal cancer, drug-tolerant persister cells, FOLFOXIRI chemotherapy, UQCRC2, lysine lactylation, SIRT1, mitophagy, oxidative phosphorylation, metabolic reprogramming, circulating tumor cells, chemotherapy tolerance, Molecular Cancer