The physical chemistry underlying condensates is elegant in its simplicity. Multivalent molecules, particularly proteins containing intrinsically disordered regions and repeated interaction motifs, can demix from the surrounding nucleoplasm or cytoplasm when their local concentrations and interaction energies cross a threshold, much like oil droplets forming in water. Early landmark studies demonstrated that germline P granules behave as liquids that localize by controlled dissolution and condensation, and subsequent work established the nucleolus as a multiphase liquid condensate and showed that super-enhancers assemble transcriptional coactivators into phase-separated compartments that link genome organization to gene control. This nucleation landscape is exquisitely sensitive to molecular composition, salt concentration, temperature, pH and post-translational modifications, meaning the cell can tune condensate formation and dissolution with impressive speed and reversibility.

Cancer exploits this tunability. The review synthesizes extensive evidence that aberrant LLPS contributes to tumorigenesis across a striking range of mechanisms. Oncogenic fusion proteins, which arise from chromosomal translocations and are common drivers of sarcomas, leukemias and brain tumors, frequently acquire prion-like low-complexity domains that promote ectopic phase separation, retargeting chromatin regulatory complexes and rewiring transcriptional programs. The BRD4-NUT fusion oncoprotein forms aberrant condensates that hijack the transcriptional machinery in NUT carcinoma, while EML4-ALK condensates in lung cancer and phase-separating NTRK fusions concentrate kinase signaling into cytoplasmic granules that fire oncogenic pathways constitutively. Disease-associated mutations in the phosphatase SHP2 promote phase separation that underlies MAPK hyperactivation, and point mutations in the chromatin reader ENL create condensate-promoting hotspots that drive leukemogenesis in vivo.

Tumor suppressors, too, are entangled with condensate biology, sometimes in paradoxical ways. The tumor suppressor SPOP normally organizes active phase-separated compartments in the nucleus, and cancer mutations disrupt these assemblies, impairing the destruction of oncogenic substrates. The histone demethylase UTX exerts its anti-tumor activity at least in part through condensation, and perturbing TET2 condensation alters genome-wide DNA methylation patterns in leukemia cells. On the oncogenic side, transcriptional co-activators YAP and TAZ, key effectors of the Hippo pathway, use phase separation to compartmentalize transcription machinery, reorganize genome topology and sustain long-term target gene expression, and interferon-gamma-driven YAP condensation has even been implicated in tumor resistance to anti-PD-1 immunotherapy. Stress granules themselves can act as oncogenic platforms, with RIOK1 phase separation restricting PTEN translation in hepatocellular carcinoma and PABPC1 condensates controlling selective translation in chronic myeloid leukemia blast crisis.

The reach of dysregulated phase separation extends into the machinery that governs innate immunity, an interface of growing therapeutic importance. The DNA sensor cGAS undergoes liquid phase condensation upon binding cytosolic DNA, activating type I interferon signaling that can either suppress tumors or, when subverted, promote tumorigenesis. Mutant NF2 induces phase separation that imprisons the cGAS-STING machinery, abrogating anti-tumor immunity, while STING itself acts as a phase-separator that can suppress innate immune signaling. Hypoxia, a defining feature of tumor microenvironments, reshapes the condensate landscape: low oxygen triggers ZHX2 phase separation that alters chromatin looping to drive metastasis, promotes FUS-circRNA stress granules that fuel autophagy in triple-negative breast cancer, and lactate-sensitive enzymes such as AARS1 modify cGAS and p53 through lactylation, tilting condensate dynamics toward tumor progression. Even metabolic states matter, as glycogen accumulation and phase separation have been shown to drive liver tumor initiation.

What elevates this review from a catalogue of mechanisms to a therapeutic manifesto is its detailed treatment of engineering strategies designed to modulate condensates directly. Among the most inventive are D-amino-acid-based interfering peptides, which exploit the protease resistance of mirror-image peptides to infiltrate and disrupt pathological condensates. Short designer peptides have already been shown to disassemble tau fibrils in models of neurodegeneration, and the same logic is being applied to oncogenic droplets. Pharmacological inhibition of SRC-1 phase separation suppresses YAP-driven transcription, targeting androgen receptor phase separation can overcome resistance to antiandrogen therapies in prostate cancer, and dissolution of oncofusion transcription factor condensates has emerged as a viable strategy for fusion-driven malignancies. Recently, targeting FOXM1 condensates reduced breast tumor growth and metastasis in preclinical models, and disruption of the KAT8-IRF1 condensate diminished PD-L1 expression, thereby promoting anti-tumor immunity.

Post-translational modifications offer a second, highly programmable axis of control. Phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, PARylation, O-GlcNAcylation and lactylation each tune the multivalent interactions that drive condensate assembly or dissolution. RNA polymerase II C-terminal domain hyperphosphorylation is itself governed by a phase-separation mechanism, and phosphorylation of HDAC6 drives aberrant chromatin architecture in triple-negative breast cancer. PARP1-mediated poly(ADP-ribosylation) can disrupt condensates to halt global transcription after DNA damage, while sirtuin-sensitive acetylation of TDP-43 drives its pathological phase separation. The review argues that post-translational modification-mimetic approaches, in which engineered molecules co-opt these chemical switches, could allow clinicians to flip condensate states in tumor cells with a specificity that traditional enzyme inhibitors have struggled to achieve against disordered proteins.

Perhaps the most forward-looking section concerns synthetic condensates as drug delivery platforms. Rather than merely dissolving harmful droplets, bioengineers are learning to build benign ones. In situ formation of biomolecular condensates can create intracellular drug reservoirs that augment chemotherapy, while coacervate vesicles assembled through LLPS improve the delivery of biopharmaceuticals, and phase-separating peptides enable direct cytosolic delivery of macromolecular therapeutics with redox-triggered release. Programmable synthetic condensates have been used to enhance translation from target mRNAs and to control cellular behavior, and intrinsically disordered region-induced condensation has improved the cytotoxicity of CAR-T cells against low-antigen cancers. Design of intrinsically disordered region-binding proteins and micropeptide killswitches that probe condensate microenvironments point toward an era in which the chemical milieux inside droplets—differences in polarity, pH and redox state—can be navigated to sharpen drug targeting and overcome resistance.

The authors are candid about the obstacles that separate this vision from routine clinical practice. Condensates lack defined binding pockets, complicating conventional structure-guided drug design, and the same material properties that make them dynamic also make them hard to model computationally. Advances in machine learning predictors such as catGRANULE 2.0, STARLING and PSPire, alongside phase-separation-directed screening and improved microscopy methods, are beginning to close the gap by identifying which condensates exist in a given tumor and which modulators shift their dynamics. The reviewers also emphasize translational design considerations, including how therapeutics partition into nuclear condensates, a factor shown to influence the efficacy of cancer drugs. By integrating biophysical insight with engineering platforms, Wang, Zhang and Zhou outline a conceptual framework in which oncogenic drivers long dismissed as undruggable—disordered transcription factors, fusion oncoproteins, scaffold proteins—can finally be engaged through the physics of their assemblies. If that framework holds up in the clinic, the liquid droplets that cancer co-opted for its own ends may become the very vulnerabilities that defeat it.

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

Article Title: Biomolecular condensates in cancer therapy

Article References: Wang, B., Zhang, L., & Zhou, F. (2026). Biomolecular condensates in cancer therapy. Nature Reviews Bioengineering. https://doi.org/10.1038/s44222-026-00493-9

Image Credits: AI Generated

DOI: 10.1038/s44222-026-00493-9

Keywords: biomolecular condensates, liquid-liquid phase separation, cancer therapy, LLPS, oncogenic fusion proteins, interfering peptides, synthetic condensates, drug delivery, post-translational modifications, tumor suppressors, Hippo-YAP signaling, bioengineering