Tumor Microenvironment Reprogramming Improves Nanomedicine-Based Chemo-Immunotherapy in Sarcomas.

Area of Science:

• Oncology
• Cancer Biology
• Nanomedicine

Background:

• Sarcomas are rare cancers with challenging treatments due to tumor microenvironment (TME) abnormalities.
• Poor TME perfusion limits drug delivery and treatment efficacy in sarcomas.
• Novel therapeutic strategies are crucial for improving sarcoma patient survival.

Purpose of the Study:

• To investigate ketotifen's efficacy in reprogramming the TME for sarcoma treatment.
• To evaluate ketotifen combined with nanomedicine-based chemo-immunotherapy.
• To explore the mechanistic basis of ketotifen's therapeutic effects.

Main Methods:

• Utilized mouse models of fibrosarcoma and osteosarcoma.
• Administered ketotifen with pegylated liposomal doxorubicin (PLD) or PLAD and anti-PD-1 antibody.
• Assessed TME changes using shear-wave elastography and contrast-enhanced ultrasound.
• Analyzed immune cell infiltration and macrophage polarization.

Main Results:

• Ketotifen reduced tumor stiffness and increased perfusion, enhancing nanomedicine efficacy.
• Combination therapy showed improved antitumor responses, particularly with alendronate.
• Ketotifen increased cytotoxic T cells and M1 macrophages, while decreasing regulatory T cells.

Conclusions:

• Ketotifen-mediated TME reprogramming improves nanomedicine-based chemo-immunotherapy in sarcomas.
• Targeting the TME offers a promising strategy to overcome treatment resistance in rare cancers.
• Combination of mechanotherapy, nanomedicine, and immunotherapy warrants further investigation.