Yondelis (trabectedin)

Based on this, the review systematically proposes innovative immunotherapy strategies targeting this key bidirectional interaction, including blocking the recruitment of TAMs (e.g., CCL2/CCR2, CXCL12/CXCR4 inhibitors), directly eliminating TAMs (e.g., CSF1R inhibitors, bisphosphonates, trabectedin), or reprogramming them into anti-tumour M1-type (e.g., CD40 agonists, TLR agonists, CD47-SIRPα axis blockers), and emphasises the great potential of combining these TAM-targeting strategies with immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1 antibodies). These combined therapies aim to synergistically enhance efficacy and overcome the current challenges of drug resistance in immunotherapy, offering new hope for more durable and effective treatment for cancer patients. Additionally, the review looks forward to the application prospects of advanced cell therapies such as nanoparticle delivery systems and chimeric antigen receptor macrophages (CAR-M) in reshaping the TME and enhancing anti-tumour immune responses, providing multi-dimensional and in-depth theoretical basis and practical directions for future cancer immunotherapy.

P2, N=100, Recruiting, Italian Sarcoma Group | Trial completion date: Dec 2025 --> Dec 2026

The findings indicate that rMETase can overcome ultra-high doxorubicin resistance in fibrosarcoma cells, likely through targeting methionine addiction, a universal metabolic vulnerability of cancer. These results support the potential clinical application of methionine restriction therapy to treat doxorubicin-resistant STS.

As a result, we identified Torin 2, talazoparib, and trabectedin as top 3 candidates with potent anti-Ewing sarcoma activity. Mechanistically, exogenous TGF-β1 was sufficient to induce resistance in tumor-only spheroids, whereas pharmacological inhibition of TGF-β1 signaling restored drug sensitivity in heterotypic spheroids. These findings establish the DCMiC platform as a low-cost, physiologically relevant system for modeling tumor-stroma interactions and enabling scalable drug discovery in clinically relevant contexts for Ewing sarcoma and other solid tumors.

Although trabectedin-olaparib combination reached the prespecified threshold for statistical significance for PFS (p<0.10), the benefit was marginal in the all-comers STS population. Nonetheless, patients affected by PARP1-expressing STS and uterine leiomyosarcoma derived substantial benefit from the combination, supporting further histology- and biomarker-driven investigation in these settings.

P=N/A, N=7, Terminated, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | Completed --> Terminated; The study was terminated prematurely due to slow recruitment after inclusion of 7 patients (of initially planned 100 patients).

Trabectedin demonstrates low disease control rate in translocation-related sarcomas, including few MCS cases. Anti-angiogenic tyrosine kinase inhibitors, such as apatinib and pazopanib, demonstrate activity in chondrosarcoma, but MCS-specific data are lacking. IDH1 inhibition benefits conventional subtypes rather than MCS. Early immunotherapy experience is limited, but pathway-directed strategies targeting BCL2 and PI3K-mTOR warrant evaluation.

P3, N=550, Completed, Italian Sarcoma Group | Active, not recruiting --> Completed

P2, N=16, Recruiting, Italian Sarcoma Group | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Aug 2025 --> Dec 2025

The chemotherapy combination was overall well tolerated, with good preservation of patients' quality of life, and no life-threatening adverse events reported.This descriptive case series of trabectedin-irinotecan in DSRCT supports preclinical evidence of synergistic activity. The regimen was well tolerated and showed potential clinical benefit even in heavily pre-treated patients, providing a rationale for further studies to optimize dosing and explore early integration.

Conventional chemotherapy may be used, with doxorubicin and dacarbazine being active though yielding poor responses. Other active drugs with currently ongoing studies in SFT are eribulin and trabectedin...An area of recent investigation is immunotherapy, with an ongoing randomized trial comparing nivolumab + ipilimumab versus pazopanib in advanced rare soft tissue sarcomas, including SFTs. Despite its rarity and therefore the difficulty in performing prospective randomized trials with a large number of patients, many promising results in perioperative (radiotherapy) or in the metastatic (medical therapy) setting have been obtained. This review overviews the main characteristics and provides the current knowledge on standard therapies.

Strategies include: (1) Reprogramming M2 to M1 phenotypes using agonists (TLR, STING, CD40) or inhibitors (STAT3/STAT6); (2) Metabolic modulation (targeting glycolysis, fatty acid oxidation, glutaminolysis); (3) Blocking recruitment axes (CCL2/CCR2, CSF-1/CSF-1R, CXCL12/CXCR4); (4) Depleting M2-TAMs (e.g., trabectedin, CAR-T cells, M2pep-drugs); (5) Enhancing phagocytosis (anti-SIRPα/CD47, anti-SIGLEC)...However, the complexity of the glioma microenvironment and blood-brain barrier necessitate combination strategies for clinical translation. Further research is needed to optimize specificity and overcome challenges like compensatory pathways and drug delivery.