How Liquid Droplets Inside Cells May Drive Cancer—and What Drugs Could Do About It

Deep inside every cell, the molecules that carry out the business of life are not evenly mixed. Instead, many proteins and RNAs spontaneously separate from their surroundings, much like oil droplets forming in water, to create membrane-less compartments called biomolecular condensates. The physical process behind this demixing, known as liquid–liquid phase separation (LLPS), has become one of the most consequential ideas in modern cell biology. Now a comprehensive review published in the journal Molecular Cancer argues that this same physics may lie at the heart of how cancers originate, resist treatment, and evade the immune system—and that targeting these droplets could open an entirely new front in oncology, provided the field first learns to separate real phase separation from look-alike phenomena.

The review, led by researchers at West China Hospital of Sichuan University, is notable for its insistence on rigor. The authors point out that while aberrant condensate behavior is increasingly implicated in cancer, many intracellular assemblies that have been attributed to LLPS have not been validated using strict experimental criteria. This matters because the cell contains many different ways of organizing matter: stable enzymatic complexes, scaffold-driven assemblies, polymer networks, and gel-like aggregates can all look like droplets under a microscope without being true liquid phases. A true LLPS droplet typically forms through weak, multivalent interactions among intrinsically disordered regions of proteins, fuses and relaxes like a liquid, exchanges components dynamically with the surrounding dilute phase, and dissolves predictably when conditions such as salt concentration, temperature, or protein concentration change. The review lays out an evidence-oriented framework for applying these criteria before labeling a structure a phase-separated condensate, a discipline the authors say the cancer field urgently needs.

At the biophysical level, condensate formation depends on a set of molecular determinants that the review examines in detail. Intrinsically disordered regions, or IDRs, are stretches of protein sequence that do not fold into a single rigid structure but instead sample many conformations. These regions carry distributed motifs—charged blocks, aromatic residues, proline-rich motifs, and arginine-glycine rich elements—that engage in multiple weak, transient interactions with one another. When the combined valence and strength of these interactions cross a threshold, the molecules demix into a dense phase enriched in those components and a dilute phase depleted of them. RNA, multivalent scaffolding proteins, and post-translational modifications such as phosphorylation, methylation, SUMOylation, and O-GlcNAcylation all tune where that threshold sits. The result is that a cell can, in principle, switch entire condensates on or off, reshape their composition, alter their viscosity, or harden them into less dynamic states without synthesizing new proteins—a degree of regulatory control that conventional signaling pathways cannot match.

Cancer exploits this control system in several ways, and the review systematically catalogues them. Mutations can add, remove, or charge-flip residues within disordered regions, shifting the phase boundary so that droplets form at concentrations where healthy cells never condense. Chromosomal translocations generate fusion proteins that stitch together a DNA-binding domain with a prion-like disordered domain, a combination notorious for driving condensate formation at oncogenic loci. Altered post-translational modification patterns, changes in RNA abundance, shifts in metabolic state, and the crowded, hypoxic, acidic environment of a tumor can all push condensates past their saturation point. The unifying theme, according to the authors, is that tumor cells do not need to invent new molecular machines; they can repurpose an existing physical mechanism of cellular organization and tilt it toward growth, survival, and spread.

The functional consequences are evaluated across five major domains of cancer biology. The first is signaling and transcription. Phase separation offers a mechanistic explanation for how transcription factors, co-activators, and the RNA polymerase machinery concentrate at specific genomic loci to form transcriptional hubs, and how signaling receptors cluster at membranes to amplify weak extracellular signals. If a tumor amplifies or mutates the multivalent components of these hubs, the hubs can become hyper-condensed, locking oncogenic programs into a permanently active state. The second domain is genome maintenance, where condensates are implicated in the response to double-strand breaks, in heterochromatin organization, and in the sequestration of repair factors. Condensate dysregulation here can either blunt DNA repair, promoting mutation accumulation, or paradoxically protect tumor cells from genotoxic therapies by concentrating repair machinery at damage sites.

The third and fourth domains—metastasis with cellular plasticity and tumor immunity—illustrate how condensate physics reaches beyond the nucleus. The review discusses how phase-separated assemblies participate in the epithelial–mesenchymal transition, cytoskeletal remodeling, and extracellular vesicle biology that enable tumor cells to detach, survive in circulation, and colonize distant tissues. On the immunity side, condensates shape the antigen presentation machinery, the formation of immune synapses in T cells, the behavior of stress granules during interferon signaling, and the cGAS–cGAMP–STING-type innate sensing pathways that determine whether a tumor looks like a threat to the immune system. A condensate that sequesters double-stranded RNA or dampens interferon-stimulated gene expression can effectively switch off the molecular alarm bells that would otherwise recruit cytotoxic T cells and natural killer cells to the tumor.

The fifth domain, therapeutic resistance, ties these mechanisms to the clinic. The review evaluates evidence that condensate formation contributes to resistance against tyrosine kinase inhibitors, PARP inhibitors, and androgen receptor pathway inhibition, among other therapies. The proposed mechanisms include the physical sequestration of drugs within dense phases, the concentration of drug targets into compartments where inhibitor penetration is poor, the buffering of inhibited pathways by condensate-stored reserves of signaling molecules, and stress granule–mediated survival programs that keep cells alive long enough to evolve durable resistance. Because these are physical, population-level phenomena rather than single gene mutations, they may explain forms of resistance that genomic sequencing alone cannot predict—adding a spatial and material dimension to the pharmacology of cancer treatment.

Perhaps the most forward-looking portion of the review concerns condensate-directed therapeutic strategies, which the authors assess explicitly according to the strength of their experimental and clinical evidence. Several classes of approach are now in play. Small molecules that partition into specific condensates can disrupt or remodel them; some such molecules have already demonstrated that selective condensate modulation is chemically achievable. Proteolysis-targeting chimeras, or PROTACs, can be designed to degrade the scaffold proteins or IDRs around which oncogenic condensates assemble. Oligonucleotide therapeutics can target the RNAs that nucleate pathological droplets. Nanoparticle platforms, including engineered particles designed to home in on and perturb specific condensates, represent a delivery-oriented strategy. The authors’ verdict, however, is deliberately cautious: the overwhelming majority of this work remains preclinical. Demonstrating that a compound dissolves a droplet in a test tube, or even in a cell line, is a long way from showing that it shrinks tumors in patients without dissolving the healthy condensates that normal cells depend on.

That caveat reflects the central challenge the review identifies for the field: specificity and validation. Cells are full of condensates that perform essential functions in nucleolar assembly, ribosome biogenesis, RNA processing, and stress adaptation, so a broadly acting condensate disruptor risks toxicity through collateral damage. Experimental validation remains difficult because phase separation in living cells is hard to prove unambiguously; methods such as live-cell imaging of fusion events, fluorescence recovery measurements, optogenetic control of multivalency, and proximity labeling are powerful but each carries its own artifacts. The authors also flag the conceptual danger of overextension, noting that the umbrella term biomolecular condensation covers a broader range of mechanisms and material states than LLPS proper, and that blurring the distinction has led the literature into claims that later scrutiny could not support. Their framework asks researchers to state which process they are actually observing and to apply matching criteria.

What emerges from the review is both a warning and a promise. The warning is that the condensate-cancer literature contains a mixture of rigorously validated LLPS mechanisms and incompletely characterized assemblies, and that therapeutic enthusiasm should be calibrated accordingly. The promise is that a genuine physical principle underlies a strikingly wide range of malignant behaviors—from oncogenic transcription to immune evasion to drug resistance—and that principle, unlike a mutation, is in principle reversible by changing the chemical environment of the cell. If the field can agree on how to prove that a droplet is a droplet, and if chemistry can deliver molecules that reshape only the condensates that matter, the energy stored in a decade of condensate biology may yet translate into the next generation of cancer therapeutics. For now, as the authors conclude, the potential remains predominantly preclinical, and the framework they propose is intended to make sure that the path from droplet to drug is followed with the same rigor that the physics itself demands.

Subject of Research: The role of liquid–liquid phase separation and biomolecular condensates in cancer mechanisms and therapy

Article Title: Liquid–liquid phase separation in cancer: mechanisms, biological functions, and therapeutic perspectives

Article References: Tang, P., Li, Y., Huang, C., Xiong, Y., Li, Y., Zhang, T., & Zhang, C. (2026). Liquid–liquid phase separation in cancer: mechanisms, biological functions, and therapeutic perspectives. Molecular Cancer. https://doi.org/10.1186/s12943-026-02798-0

Image Credits: AI Generated

DOI: 10.1186/s12943-026-02798-0

Keywords: liquid–liquid phase separation, biomolecular condensates, cancer biology, intrinsically disordered regions, therapeutic resistance, transcriptional condensates, tumor immunity, metastasis, PROTACs, drug discovery, Molecular Cancer, condensate dysregulation