The different STS subtypes exhibit molecular heterogeneity. Nacev et al. identified specific somatic mutations and copy number alterations in some subtypes via the genetic sequencing of STS samples, and compared tumor mutational burden and microsatellite instability across the different subtypes (3). STS can be divided into two genomic categories. One category (80%) consists of tumors with complex karyotypes, such as leiomyosarcoma, undifferentiated pleomorphic sarcoma, DDLPS, and anigosarcoma. These tumors are characterized by many gene rearrangements and chromosomal gains or losses that often include cell cycle–related genes such as TP53, MDM2, RB1, and CDK4 (4). The other category (20%) consists of tumors with specific genetic alterations, such as gene translocations and activating point mutations (5). Importantly, tumors with specific genetic alterations can also develop complex karyotypes as the tumor progresses. Taylor et al. reported that different subtypes of retroperitoneal liposarcoma (RPL) have distinct genomic landscapes, and discussed the genomic differences between RPL and extremity LPS (6).

WDLPS and DDLPS share several common genetic features. Research by Wagner and his team indicates that WDLPS and DDLPS evolve from common precursors into distinct patterns (7). The molecular signatures of both subtypes are characterized by amplifications in the 12q13-15 region on the long arm of chromosome 12 (8). Molecular testing indicates that approximately 90% of WDLPS/DDLPS cases have confirmable MDM2 and CDK4 gene amplifications, which are the primary driver genes (9). In recent years, an increasing number of whole-genome sequencing studies have identified that additional gene amplifications within the 12q13-15 region in WDLPS/DDLPS (such as the amplification of HMGA2, TSPAN31, FRS2, GLI1, YEATS4, YEATS2, NAV3, and CPM in WDLPS), new genes outside the 12q13-15 region (such as DDR2 and SDHC in WDLPS, and FGFR3 in DDLPS), and receptor tyrosine kinase (RTK)-related signaling pathways are closely associated with the occurrence and progression of WDLPS/DDLPS (10–12).

Given the shared genetic characteristics between DDLPS and WDLPS, and the observation of both well-differentiated and poorly differentiated areas in many DDLPS samples, DDLPS is commonly believed to evolve from WDLPS. However, these two sarcomas differ substantially. During dedifferentiation, ongoing DNA damage leads to genomic instability and the further accumulation of complex genomic aberrations. In DDLPS, pathways related to cell proliferation and the DNA damage response are upregulated, whereas in WDLPS, pathways related to adipocyte differentiation and metabolism are upregulated (13). Studies have also reported that the loss of 11q23 and the amplification of 6q23 or 1q32 (or the co-amplification of 6q23 and 1q32) are DDLPS-specific genomic abnormalities. Additionally, intrachromosomal and interchromosomal gene rearrangements and gene fusions (such as C15orf7::CBX3, CTDSP1::DNM3OS, and CTDSP2::DNM30S) have been identified in DDLPS but not in WDLPS. DDIT3 is also amplified in DDLPS patients (14). Furthermore, a study that comprehensively analyzed the molecular characteristics of retroperitoneal sarcoma-WDLPS revealed that FOXD4L3 has periodic mutations that interact with the PAX pathway to promote tumorigenesis. Moreover, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways, as well as genes associated with the transition from an adipose to a “tumor” phenotype, are all dysregulated (15). Pollock et al. reported that Aurora A kinase (AURKA) is significantly overexpressed in retroperitoneal sarcoma-DDLPS and is strongly associated with metastasis and recurrence (16). Combined, large-scale whole-exome and RNA sequencing in Japan has revealed that somatic copy number alterations are the most common genomic mutations in DDLPS (17). The frequency of mutations varies for each chromosome, ranging from 0.114 (chromosome 21) to 0.482 (chromosome 12). In this study, DDLPS was then divided into the following three groups based on the associations between somatic copy number alterations and clinical features: cluster 1, with only 12q15 high magnification; cluster 2, with 12q15 and 1p32.1 high magnification; and cluster 3, without 12q15 high magnification. A survival analysis conducted after the genomic clustering revealed that, compared with cluster 1 patients, cluster 2 DDLPS patients had better progression-free survival (PFS) rates. Multivariate regression analysis revealed that cluster 1 was a significant predictor of poor PFS, independent of the surgical margin and primary tumor site. Furthermore, a comparative analysis of WDLPS and DDLPS components revealed that the gene sets associated with cell cycle progression, including the G2/M checkpoint and E2F target genes, were significantly enriched in DDLPS. By contrast, a gene set associated with adipocyte differentiation or lipid metabolism, including adipogenesis and fatty acid metabolism, was significantly enriched in WDLPS.

Lago et al. reported that DNA G-quadruplexes (G4s) in the promoters of lipopolysaccharide-treated cells are associated with high transcription levels in open chromatin, indicating that promoter G4s and related transcription factors work in concert to form cell-specific transcriptional programs (18). Moreover, Richter et al. reported that mouse double minute 2 homolog (MDM2) induces the formation of stable G-quadruplexes, which are specifically recognized by cellular helicases. The targeting of G-quadruplexes can reduce MDM2 expression and p53 degradation, thereby promoting cell cycle arrest and apoptosis in cancer cells (19).

MLPS is genetically characterized by the translocation of t(12;16)(q13;p11) in more than 95% of cases; this results in the FUS-DDIT3 fusion gene, which stimulates cell proliferation and disrupts adipogenic differentiation (20). The remaining 5% of MLPS cases are genetically characterized by the translocation of t(12;22)(q13;q12), which results in the EWSR1-DDIT3 fusion gene (20). These features are considered unique to MLPS. Additionally, high RET expression has been observed in MLPS, and approximately 25% of all cases have mutations that activate the PI3K/AKT/mammalian target of rapamycin (mTOR) signaling pathway (21). Moreover, over 50% of MLPS cases carry mutations in the TERT promoter (22).

PLPS is characterized by marked chromosomal abnormalities, including chromosomal deletions and duplications (23). Although related molecular research is limited, studies have reported that mutations or inactivation of RB1 are associated with PLPS development (24). Furthermore, genetic testing of a metastatic lesion in a patient with uterine PLPS with liver metastasis revealed an IQGAP-NTRK3 gene fusion (25).

Myxoid pleomorphic LPS exhibits complex chromosomal changes; however, it lacks the FUS-DDIT3 gene fusion that is characteristic of MLPS and the MDM2/CDK4 gene amplification found in DDLPS (2). Molecular research in this area is also limited.

Proteomic technologies and strategies are increasingly being applied to the study of STS. Huang et al. conducted proteomic analyses of different STS subtypes. By mining the proteomic data of cluster of differentiation 3 (CD3)⁺ tumor-infiltrating lymphocyte (TIL) groups in patients with DDLPS, these authors revealed that the high CD3⁺ TIL group was enriched in aspects such as T-cell activation, T-cell receptor signaling, leukocyte proliferation, cell adhesion, and the interferon response. By contrast, the low-CD3⁺ TIL group was enriched in the complement cascade, with an active complement system. These findings support the future evaluation of combination therapy with anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint inhibitors and complement inhibitors to treat DDLPS patients in the low CD3⁺ TIL group (26, 27). Moreover, the data from this study suggest that, at the protein level, cyclin-dependent kinase 4 (CDK4) is expressed at a relatively high level in DDLPS. This finding is consistent with the amplification of CDK4 in many DDLPS, although no enriched ontology was observed in an overexpression analysis of DDLPS. It has also been reported that vesicular trafficking proteins are an independent prognostic factor for distant metastasis. In addition, through the joint analysis of proteomic and phosphorylation data, a team led by Ding demonstrated STS subtypes with different molecular characteristics and clinical outcomes, and identified the key driving molecules for STS metastasis and proliferation (28). Fat metabolism-related pathways, peroxisome proliferator–activated receptor (PPAR) pathways, and vitamin metabolism pathways are significantly upregulated in DDLPS and MLPS. Furthermore, the PI3K/AKT/mTOR signaling pathway was significantly upregulated in DDLPS. Numerous molecular markers associated with pathological subtypes were also validated, including CDK4 in DDLPS. Notably, this study conducted an integrated analysis of histopathological subtypes, a hierarchical clustering of pathological subtypes, a proteomic analysis of subtypes, and an analysis of immune subtypes. The findings revealed the relationships between STS subtypes under different classification criteria, as well as their respective molecular, pathway, and clinical characteristics. In this integrated analysis, a detailed division of STS was noted, and STS heterogeneity was explored in great detail.

Together, these findings indicate that LPS has extensive molecular heterogeneity. Further exploration and discoveries of molecular differences and unique molecular characteristics will provide a wide range of ideas and directions for the experimental design and treatment of LPS.

Kirtonia et al. reported that many oncogenic long noncoding RNAs, including MALAT1, PVT1, SNHG15, LINC00152, and MIR210HG, are differentially expressed in LPS (61). Similarly, Yuhong et al. reported that LINC00423 expression is downregulated in retroperitoneal sarcoma; this is primarily caused by the disruption of NFATC3 stability, thus activating the MAPK signaling pathway (62).

Cancer-derived extracellular vesicles facilitate intercellular communication and transport bioactive molecules within the tumor microenvironment to impact tumor occurrence, progression, and metastasis. In RPL-DDLPS, extracellular vesicles carrying “cargo” MDM2 are released into the microenvironment, and MDM2 DNA from RPLPS is transferred to target recipient cells—preadipocytes—in the tumor microenvironment. This transfer leads to impaired p53 activity and increased matrix metalloproteinase 2 (MMP2) production in preadipocytes, which is involved in tumor cell dissemination and recurrence (63, 64).

A phase I study of the MDM2 inhibitor milademetan included 48 patients with recurrent or refractory WDLPS/DDLPS, with a median PFS (mPFS) of 6.3 months; one DDLPS patient achieved a partial response (69). The MANTRA study compared the efficacy of milademetan with that of trabectedin in 178 patients with unresectable or metastatic DDLPS who had failed to respond to prior treatments. No significant differences in mPFS were observed (3.6 months vs. 2.2 months, respectively), the median overall survival was comparable (9.5 months vs. 10.2 months, respectively), and the objective response rate did not significantly differ (4.7% vs. 3.4%, respectively) between the two treatments. On the basis of these findings, the MDM2 inhibitor failed as a second-line treatment for DDLPS (70).

A phase Ia study evaluated the efficacy of the MDM2-p53 antagonist brigimadlin in the treatment of 54 patients with advanced/metastatic MDM2-amplified and TP53 wild-type solid tumors. The overall objective response rate was 11.1% (6 of 54), the disease control rate was 74.1% (40 of 51), and the mPFS was 8.1 months. These findings indicate that brigimadlin has potential antitumor activity in patients with DDLPS and WDLPS. In the phase Ib (dose expansion) study, the number of evaluable DDLPS patients increased to 76 cases, with a preliminary mPFS of 8.1 months (95% confidence interval: 5.7–13.6 months), an objective response rate of 19%, and a disease control rate of 85%. Moreover, in the five evaluable WDLPS patients, the disease control rate was 100% (71). A phase II/III global multicenter study comparing brigimadlin with doxorubicin as first-line treatments for advanced DDLPS patients is currently underway (Clinical Trial: NCT05218499).

A phase II clinical study of palbociclib in 59 patients with WD/DDLPS revealed an mPFS of 17.9 weeks, with one patient achieving a complete response that lasted over 2 years. Thirty-six percent of the patients experienced grade 3–4 neutropenia (72). In 61 patients with retroperitoneal WDLPS/DDLPS treated with the single agent palbociclib, the practical application and surgical outcomes were as follows. The mPFS for WDLPS and DDLPS patients were 9.2 and 2.6 months, respectively. In addition, 12 patients ultimately underwent surgical resection, with half of the patients achieving R0/R1 resection; however, surgery did not improve overall survival (73).

Higuchi et al. reported that a combination of palbociclib and recombinant methioninase enhanced the efficacy of palbociclib against DDLPS in a patient-derived orthotopic xenograft mouse model of LPS (74). Moreover, a phase II clinical study of patients with recurrent or metastatic DDLPS treated with abemaciclib reported an mPFS of 30.4 weeks, with two patients achieving a partial response (75).

A phase Ib study combined siremadlin (a p53-MDM2 inhibitor) with ribociclib (a CDK4/6 inhibitor) in 74 patients with advanced WDLPS and DDLPS. Three patients achieved a partial response and 38 patients had stable disease, thus demonstrating the good antitumor activity of this combination treatment (76).

PARP1 expression is heterogeneous across subtypes. High PARP1 expression is mostly found in leiomyosarcoma, is often found in Grade 3 CINSARC (Complexity INdex in SARComas) and high-risk tumors, and is associated with a shorter MFS. By contrast, low PARP1 expression is mostly found in LPS and MFS (77). A multicenter, randomized, controlled phase II clinical study (TOMAS2) explored the efficacy of trabectedin combined with the PARP inhibitor olaparib versus trabectedin alone in 130 adult patients with STS whose previous treatments had failed. Of these, 67 patients had an L-sarcoma (LPS/leiomyosarcoma) subtype. The subgroup analysis did not yield positive results for mPFS or overall survival (78).

Zaffaroni et al. reported that selinexor (a selective XPO1 inhibitor) has stronger antitumor activity than doxorubicin against retroperitoneal DDLPS patient-derived xenografts (79). A phase Ib study of selinexor in the treatment of advanced STS included 15 DDLPS patients. Six patients experienced a reduction in the target lesion size and seven patients achieved stable disease as the best response; this was maintained for at least 4 months (80). A subsequent study, SEAL, included 285 patients with advanced DDLPS who had previously received two to three lines of treatment, and reported an mPFS of 2.8 months. The most common grade 3–4 adverse events associated with selinexor use were nausea (80.7%), decreased appetite (60.4%), and fatigue (51.3%) (81). Another study demonstrated that selinexor treatment can help to control pain and improve quality of life in patients with advanced DDLPS (82).

In the ALTER-0202 study, 13 patients with recurrent/metastatic advanced LPS were treated with anlotinib. This treatment resulted in a 12-week progression-free rate of 63%, and mPFS and median overall survival times of 5.6 and 13 months, respectively (83). The ALTER-S006 study revealed that anlotinib maintenance treatment resulted in an mPFS of 9.1 months in 49 STS patients who achieved a partial response or stable disease after at least four cycles of first-line anthracycline-based chemotherapy; LPS patients had an mPFS of 12.5 months (84). In another retrospective study, 17 patients with metastatic/recurrent WDLPS/DDLPS who were treated with anlotinib had an mPFS of 27.9 weeks, a 24-week progression-free rate of 58.8%, and an overall survival of 56.6 weeks (85). The aforementioned studies indicate the good efficacy of anlotinib for LPS, and the use of anlotinib as a second-line treatment for patients with STS is included in the Chinese Society of Clinical Oncology guidelines.

The National Comprehensive Cancer Network guidelines recommend pazopanib as a second-line treatment option for patients with STS (86). In a phase II study, pazopanib was used to treat 41 patients with LPS (27 with DDLPS). This treatment resulted in a 12-week progression-free rate of 68.3%, and for DDLPS patients, the mPFS was 6.24 months (87). A multicenter phase II randomized controlled trial in Germany compared the efficacy of combined pazopanib and gemcitabine with pazopanib alone in the treatment of 90 patients with refractory STS (19% with LPS). There was a 12-week PFS of 74% vs. 47%, an mPFS of 5.6 months vs. 2.0 months, and an overall survival of 13.1 months vs. 11.2 months, respectively. However, the objective response rate was generally low, at 11% vs. 5%, respectively (88). Similarly, a previous study revealed that preoperative pazopanib treatment for nonmetastatic, resectable, high-risk STS did not benefit patients (89). In addition, in the SARC024 study, regorafenib treatment did not yield positive results for mPFS or overall survival in 48 patients with advanced LPS (90).

In summary, many types of targeted drugs have been used in the exploration of clinical treatments, and have achieved different results. Nonetheless, through continuous in-depth research, more accurate targets are expected to be obtained. The ultimate goal is to develop new drugs and novel solutions to improve the quality of life and survival of patients.