Background

The spatial and temporal coordination of biochemical reactions is crucial for cellular physiology [1]. While membrane-bound organelles are essential for spatially organized cellular processes, the discovery of membrane-less organelles (MLOs) has shed light on new mechanisms for tightly controlling processes within cells [2]. MLOs, as known as biomolecular condensates (BMCs), include the nucleolus [2], Cajal bodies [3], nucleoli [4], stress granules (SGs) [5,6,100]. Notably, the Lys residues within the IDRs are particularly prone to get SUMOylation, a modification that significantly contributes to the formation of the promyelocytic leukemia nuclear bodies (NBs). De-SUMOylation can lead to the release of a constituent protein and the separation of NBs during mitosis [101, 102].

Given the complexity of physicochemical conditions, the manipulation of PTMs is an intriguing approach to influence LLPS. Thus, it is pivotal to understand the possible mechanisms in cancer-related PTMs associated with LLPS (Table 2).

Table 2 Summary of cancer-related PTMs involved in LLPS
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Deregulated phase separation in cancer

Emerging evidence has robustly revealed that aberrant BMCs are involved in various biochemical processes in human diseases and various oncogenic signaling pathways [19] (Table 3). Next, we review the role of LLPS in tumors based on several hallmarks (Fig. 4).

Table 3 Oncogenic signaling assosciated condensates that were involved in LLPS
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Fig. 4
figure 4

Summary of deregulated phase separations in cancer. A RTK granule formations activate RTK/MAPK signaling pathways to promote tumor proliferation. B DDX21phase separation activates MCM5, facilitating EMT signaling and modulating metastasis of colon cancer. C LLPS of 53BP1 diminish downstream targets of p53 to evade growth suppressions. D The accumulation of 53BP1 in the nuclear foci is enhanced after DNA damage, activating p53 and regulating cellular senescence. E SUMO ALT-associated PML bodies on the telomeres facilitate the replicative immortality of cancer cells. F Nuclear condensates (nYACs) generated through the LLPS of YTHDC1 (binding with m6A-mRNA) are significantly increased in AML cells. G Mutations in the FERM domain of NF2 (NF2m) robustly inhibited STING-initiated antitumor immunity by forming NF2m-IRF3 condensates. H PML nuclear bodies (NBs) serve as comprehensive ROS sensors associated with antioxidative pathways. I EBNA2 becomes part of BMCs and regulates EBV gene transcriptions. J BRD4 forms condensates with SEs to regulate angiogenesis. K NUP98-HOXA9 fusion proteins attenuate aberrant chromatin organizations. L m6A-modified androgen receptor (AR) mRNA phase separated with YTHDF3 responds to AR pathway inhibition (ARPI) stress in prostate cancers. M LLPS of GIRGL-CAPRIN1-GLS1 mRNA suppresses GLS1 translation and adapts to an adverse glutamine-deficient environment. N icFSP1 induces FSP1 condensates to trigger ferroptosis in the dedifferentiation of cancer cells

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LLPS promotes the proliferation of cancer cells

Cancer cells can undergo unrestricted division [20, 133,134,135,136], which can occur through gene mutations that activate oncogenic receptor tyrosine kinases (RTKs) and the downstream MAPK signaling involving RAS proteins.

Adaptor proteins involved in RTK and RAS signaling, such as LAT, GRB2 and SOS, undergo phase separation during RTK activation [Full size image

Modifications of PTMs and physicochemical conditions

As previously mentioned, certain post-transitional modifications and physiochemical conditions contribute to LLP dynamics (Fig. 5B). For example, nYACs protect mRNAs from degradation and strengthen the role of YTHDC1 in leukemogenesis, which inspires us to disrupt m6A to violate deleterious condensates[105]. Further, studies have reported that modulating PTMs in LLPS proteins is also significant [25, 96, 102, 218,219,220,221]. In the case of colon cancer, SENP1 has been reported to decrease RNF168 SUMOylation, inhibit nuclear condensate formation, and promote DNA damage repair (DDR) and drug resistance. Given these observations, strategies to curb the harmful effects of protein aggregation by influencing protein modifications warrant further investigation.

Drug interventions of the dynamics of condensates

Drugs can significantly influence the dynamics of the condensates, affecting their anticancer effects and potentially leading to drug resistance (Fig. 5C). For example, in luminal breast cancer, tamoxifen accumulates in MED1 condensates, preventing the incorporation of ERα into these condensates, partially inhibiting cancer progression. However, when MED1 is overexpressed, larger condensates dilute the drug concentration, ultimately leading to the development of resistance [202]. Several drugs, such as cisplatin, mitoxantrone, and THZ1, selectively partition into BMCs formed by MED1 (Table 4). Drug resistance can occur via selective partitioning into BMCs or changes in properties. Notably, cisplatin exerts its anticancer activity by dissolving SEs, indicating that changes in the condensate properties may improve therapeutic outcomes[202]. This finding highlights the potential of altering the properties of condensates to improve therapeutic outcomes. In some cases, promoting the formation of BMCs may have therapeutic effects. For example, in APL, fusion proteins of PML-retinoic acid receptor α (RARA) hinder the assembly of PML bodies and result in the suppression of differentiation genes. Successful APL treatment involves the restoration of PML nuclear bodies using empirically discovered drugs (Table 4) [222].

Roles of LLPS in vesicular trafficking and drugs’ delivery

Although LLPS and traditional vesicles are two different concepts with distinctive definitions, the vesicular trafficking role of LLPS is still rarely described and attractive. Conventional approaches typically utilize nanoscale carriers that are confined within the compartments of the intranuclear body. Nevertheless, recent findings have demonstrated that micron-scale polypeptide clusters, formed through phase separation, possess the ability to traverse the cell membrane via a non-canonical endocytic pathway. These clusters undergo glutathione-induced release of their cargo and exhibit the capacity to rapidly incorporate various macromolecules into microdroplets, such as RNA, small peptides and enzymes [223]. Loaded with polysomes, they can provide new approaches for vaccine carriers based on mRNAs and intracellular transportations for cancer treatments.

Likewise, as previously mentioned, droplets of drugs formed by LLPS can unexpectedly raise the inner drug concentration up to 600 times higher than that outside the condensate [202]. Furthermore, MED1 predominantly acts on oncogene promoters, thereby enabling cisplatin to ultimately target the corresponding DNA through its toxic platinum atoms, effectively assaulting the vital components of the cancer cells. Besides, the phosphopeptide KYp has been observed to induce LLPS level at the cell membrane, thus enhancing the permeation and internalization of the peptide drug [224]. KYp has the ability to interact with alkaline phosphatase, resulting in the dephosphorylation and in situ self-assembly at the cell membrane [224]. The process induces the aggregation of alkaline phosphatase and the separation of proteolipid phases at the membrane, ultimately enhancing membrane leakage and facilitating the entry of the peptide drug. These great discoveries provide inspirations for designing drug delivery systems and more similar ideas are worth exploring.