Spatiotemporal Sequential Delivery of Chidamide Regulates Macrophage Reprogramming in Lymphoma Microenvironment...

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Tumor-associated macrophages (TAMs) promote an immunosuppressive microenvironment and contribute to diffuse large B-cell lymphoma (DLBCL) relapse.
• The molecular mechanisms regulating DLBCL-TAMs and potential therapeutic interventions remain unclear.

Purpose of the Study:

• To investigate the role of histone deacetylases (HDACs) and STAT3 deacetylation in M2 macrophage accumulation in DLBCL.
• To develop a targeted drug delivery system for chidamide to overcome its adverse effects and improve DLBCL treatment.

Main Methods:

• Investigated HDACs-induced STAT3 deacetylation in DLBCL-TAMs.
• Developed peptide-modified extracellular vesicles (M2pep-EVs) for M2 macrophage targeting.
• Loaded chidamide into M2pep-EVs combined with pH-responsive hydrogel (TSPBA/PVA) for in situ release (Chid@M2pep-EVs).

Main Results:

• HDACs-induced STAT3 deacetylation was critical for M2 macrophage accumulation in DLBCL.
• Chid@M2pep-EVs demonstrated targeted delivery to M2 macrophages, inhibiting HDACs and enhancing STAT3 acetylation.
• The system reprogrammed M2 macrophages to M1 phenotype, suppressed lymphoma growth in vivo, and reduced adverse reactions.

Conclusions:

• Chidamide delivery via M2pep-EVs offers a promising strategy for treating refractory/relapsed DLBCL.
• Targeted inhibition of HDACs and reprogramming of TAMs can overcome lymphoma immunosuppression.
• This approach provides a translational strategy with reduced dosage and side effects for lymphoma therapy.