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Anthraquinone-Loaded Liposomes for TAM Reprogramming in Triple-Negative Breast Cancer: Mechanistic Rationale,
Limin Zhai1, Juan Liu1, Lizhen Mu1
1Innovative Chinese Medicine Research Institute, Department of Pharmacy, Shanghai Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China.
Abstract:
Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by limited actionable targets, early recurrence, metastatic propensity, and variable responses to immune checkpoint blockade. Therapeutic resistance is closely associated with myeloid immunosuppression, in which tumor-associated macrophages (TAMs) promote T-cell exclusion, stromal remodeling, angiogenesis, metabolic dysfunction, and resistance to cytotoxic and immune-based therapies. Anthraquinone compounds, including emodin, aloe-emodin, rhein, and chrysophanol, may support TAM reprogramming by regulating tumor-cell stress responses, endoplasmic reticulum stress, immunogenic cell death-associated signaling, redox balance, immunometabolism, and STAT3/NF-κB-related inflammatory pathways. However, poor aqueous solubility, heterogeneous biodistribution, unstable systemic exposure, and potential off-target toxicity limit their translational development. Liposomal delivery offers a formulation strategy to improve solubilization, biodistribution, TAM-associated uptake/engagement, intracellular release, and therapeutic exposure windows. This review discusses anthraquinone-loaded liposomes for TAM reprogramming in TNBC by integrating mechanistic rationale, evidence boundaries, delivery logic, formulation determinants, and translational challenges, with particular attention to stress chaperone proteins, lipid composition, vesicle lamellarity, membrane phase state, responsive release, clinically relevant liposomal formulations, and clinical developability. Overall, anthraquinone-loaded liposomes are better positioned as immune microenvironment recalibration platforms or synergistic modulators in combination therapy rather than as standalone cytotoxic agents for TNBC.
Insights
Anthraquinone-loaded liposomes show promise for reprogramming tumor-associated macrophages in triple-negative breast cancer (TNBC). This approach aims to overcome therapeutic resistance by modulating the tumor immune microenvironment, rather than acting as standalone cytotoxic agents.
Area of Science:
- Oncology
- Immunology
- Nanomedicine
Background:
- Triple-negative breast cancer (TNBC) is aggressive with limited treatment options and frequent recurrence.
- Therapeutic resistance in TNBC is linked to myeloid immunosuppression, particularly tumor-associated macrophages (TAMs), which hinder anti-cancer immune responses.
- Anthraquinones show potential for TAM reprogramming, but formulation challenges limit their clinical use.
Purpose of the Study:
- To review the potential of anthraquinone-loaded liposomes for TAM reprogramming in TNBC.
- To integrate mechanistic rationale, delivery strategies, and formulation considerations for liposomal anthraquinones.
- To discuss translational challenges and clinical developability of this therapeutic approach.
Main Methods:
- Literature review integrating mechanistic insights on anthraquinones and liposomal delivery.
- Analysis of factors influencing liposomal formulation, including lipid composition and release mechanisms.
- Evaluation of TAM reprogramming pathways modulated by anthraquinones, such as stress responses and immunometabolism.
Main Results:
- Liposomal delivery can overcome anthraquinones' poor solubility, biodistribution, and toxicity issues.
- Anthraquinones can modulate TAMs by influencing stress pathways, redox balance, and inflammatory signaling (e.g., STAT3/NF-κB).
- Liposomal formulations offer improved control over drug release and therapeutic exposure.
Conclusions:
- Anthraquinone-loaded liposomes are promising for recalibrating the tumor immune microenvironment in TNBC.
- These liposomes are better suited as immune modulators in combination therapies than as standalone treatments.
- Further research into formulation optimization and clinical developability is warranted for effective TNBC treatment.
