Changshu No.1 People's Hospital

Breast cancer (BC) remains a major global health challenge, with significant mortality despite advancements in conventional therapies. Immunotherapy, particularly through engineered macrophages, is emerging as a promising strategy for BC treatment. Macrophages play key roles in both tumor progression and immune modulation within the tumor microenvironment (TME). This review explores current engineering techniques to enhance the therapeutic potential of macrophages in BC immunotherapy. We discuss cytokine engineering, tumor-targeting receptors like chimeric antigen receptor (CAR)-macrophages, and novel drug delivery platforms, including engineered macrophages as direct drug carriers and as carriers for nanoparticles. The review also addresses the challenges in translating these strategies to clinical applications and highlights future directions for improving therapeutic outcomes in BC.

Plasmacytoid dendritic cells (pDCs) are crucial components of the immune response during viral infections, yet their function and development in the late phase of sepsis remain poorly understood. In this study, we investigated the impact of prolonged sepsis on pDCs and their progenitors in cecal ligation and puncture (CLP)-induced septic mice. We observed a significant reduction in both pDCs and their progenitors, alongside the presence of mature and regulatory pDCs. These mature and regulatory pDCs exhibited impaired type I interferon (IFN) secretion and antigen presentation capacity. In a Flt3L culture system of hematopoietic stem/progenitor cells (HSPCs) from CLP and Sham mice, we found that CLP-derived HSPCs exhibited an impaired ability to generate immunocompetent pDCs, as evidenced by lower IFN-α expression and reduced pDC recovery. Further investigation revealed downregulation of the key transcription factor TCF4 during pDC differentiation in these progenitor cells. Ectopic expression of TCF4 in these progenitors restored pDC generation. Additionally, we observed elevated levels of granulocyte colony-stimulating factor (G-CSF) in the bone marrow supernatant of septic mice. The addition of G-CSF to the culture system significantly impaired the generation of immunocompetent pDCs from HSPCs of normal mice. These findings suggest that sepsis may impair the production of immunocompetent pDCs from HSPCs by modulating key genes involved in pDC differentiation, potentially contributing to immune suppression and increased susceptibility to opportunistic infections in the later stages of sepsis.

This study evaluated the lymphangiogenesis-promoting and antifibrotic effects of PA, a natural component derived from Poria cocos, and to explore its mechanisms to mitigate lymphedema progression.

Tubule formation, spheroid sprouting, cell scratch and transwell assays approaches were used to assess the effects of TGF-β1 and PA on LECs tube formation and migratory capacity. A lymphedema tail loop mouse model was constructed, with tail volume measurements, H&E staining, Masson staining, immunofluorescence, and Western blotting to compare fibrosis and lymphatic vessel neogenesis under PA-treated and untreated conditions. RNA sequencing was employed for transcriptomic analysis, while immunofluorescence and Western blotting were used to investigate the role of the AA-EETs-DHETs pathway in PA-mediated lymphatic repair and the associated mitigation of fibrosis.

Functionally, it enhanced LECs tube formation, sprouting, and migration, while reducing collagen III and α-SMA deposition in both TGF-β1-induced fibrosis and mouse models, alleviating the fibrotic microenvironment. Mechanistically, PA exerted its effects by modulating the AA-CYP2C8/CYP2J2-EETs-sEH-DHETs metabolic pathway, thereby increasing EETs level.

PA promotes lymphangiogenesis and alleviates LECs fibrosis by increasing EETs level, highlighting its potential as a novel therapeutic target for lymphedema.