P=N/A, N=10, Recruiting, West China Hospital, Sichuan University; WestVac Biopharma Co.,Ltd.

P1, N=10, Recruiting, Columbia University | Trial primary completion date: Dec 2025 --> Dec 2026

P4, N=62, Not yet recruiting, University of Sao Paulo General Hospital

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=40, Completed, University of Utah | Enrolling by invitation --> Completed

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

P1, N=20, Recruiting, University Hospital, Toulouse | Trial completion date: Oct 2025 --> Dec 2026 | Trial primary completion date: Oct 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.

P2, N=1, Terminated, Nantes University Hospital | N=50 --> 1 | Trial completion date: Nov 2026 --> Dec 2025 | Recruiting --> Terminated | Trial primary completion date: Nov 2026 --> Dec 2025; Recruitment difficulties

P2, N=30, Terminated, Shuttle Pharmaceuticals, Inc. | N=54 --> 30 | Trial completion date: Feb 2027 --> Dec 2025 | Recruiting --> Terminated | Trial primary completion date: Aug 2026 --> Dec 2025; Terminated due to the sponsor's decision.

P1, N=21, Active, not recruiting, National Cancer Institute (NCI) | N=42 --> 21 | Trial completion date: Dec 2025 --> Dec 2026

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.