Dendritic cells (DCs) orchestrate the initiation, programming, and regulation of anti-tumor immune responses. Emerging evidence indicates that the tumor microenvironment (TME) induces immune dysfunctional tumor-infiltrating DCs (TIDCs), characterized with both increased intracellular lipid content and mitochondrial respiration. The underlying mechanism, however, remains largely unclear. Here, we report that fatty acid-carrying tumor-derived exosomes (TDEs) induce immune dysfunctional DCs to promote immune evasion. Mechanistically, peroxisome proliferator activated receptor (PPAR) α responds to the fatty acids delivered by TDEs, resulting in excess lipid droplet biogenesis and enhanced fatty acid oxidation (FAO), culminating in a metabolic shift toward mitochondrial oxidative phosphorylation, which drives DC immune dysfunction. Genetic depletion or pharmacologic inhibition of PPARα effectively attenuates TDE-induced DC-based immune dysfunction and enhances the efficacy of immunotherapy. This work uncovers a role for TDE-mediated immune modulation in DCs and reveals that PPARα lies at the center of metabolic-immune regulation of DCs, suggesting a potential immunotherapeutic target.

Targeting the TGF-β1 pathway for breast cancer metastasis therapy has become an attractive strategy. We have previously demonstrated that naringenin significantly reduced TGF-β1 levels in bleomycin-induced lung fibrosis and effectively prevented pulmonary metastases of tumors. This raised the question of whether naringenin can block TGF-β1 secretion from breast cancer cells and inhibit their pulmonary metastasis. We transduced a lentiviral vector encoding the mouse Tgf-β1 gene into mouse breast carcinoma (4T1-Luc2) cells and inoculated the transformant cells (4T1/TGF-β1) into the fourth primary fat pat of Balb/c mice. Pulmonary metastases derived from the primary tumors were monitored using bioluminescent imaging. Spleens, lungs and serum (n = 18–20 per treatment group) were analyzed for immune cell activity and TGF-β1 level. The mechanism whereby naringenin decreases TGF-β1 secretion from breast cancer cells was investigated at different levels, including Tgf-β1 transcription, mRNA stability, translation, and extracellular release. In contrast to the null-vector control (4T1/RFP) tumors, extensive pulmonary metastases derived from 4T1/TGF-β1 tumors were observed. Administration of the TGF-β1 blocking antibody 1D11 or naringenin showed an inhibition of pulmonary metastasis for both 4T1/TGF-β1 tumors and 4T1/RFP tumors, resulting in increased survival of the mice. Compared with 4T1/RFP bearing mice, systemic immunosuppression in 4T1/TGF-β1 bearing mice was observed, represented by a higher proportion of regulatory T cells and myeloid-derived suppressor cells and a lower proportion of activated T cells and INFγ expression in CD8+ T cells. These metrics were improved by administration of 1D11 or naringenin. However, compared with 1D11, which neutralized secreted TGF-β1 but did not affect intracellular TGF-β1 levels, naringenin reduced the secretion of TGF-β1 from the cells, leading to an accumulation of intracellular TGF-β1. Further experiments revealed that naringenin had no effect on Tgf-β1 transcription, mRNA decay or protein translation, but prevented TGF-β1 transport from the trans-Golgi network by inhibiting PKC activity. Naringenin blocks TGF-β1 trafficking from the trans-Golgi network by suppressing PKC activity, resulting in a reduction of TGF-β1 secretion from breast cancer cells. This finding suggests that naringenin may be an attractive therapeutic candidate for TGF-β1 related diseases.

Breast cancer (BrCa) is the malignant tumor that most seriously threatens female health; however, the molecular mechanism underlying its progression remains unclear. Here, we found that conditional deletion of HIC1 in the mouse mammary gland might contribute to premalignant transformation in the early stage of tumor formation. Moreover, the chemokine CXCL14 secreted by HIC1-deleted BrCa cells bound to its novel cognate receptor GPR85 on mammary fibroblasts in the microenvironment and was responsible for activating these fibroblasts via the ERK1/2, Akt, and neddylation pathways, whereas the activated fibroblasts promoted BrCa progression via the induction of the epithelial–mesenchymal transition (EMT) by the CCL17/CCR4 axis. Finally, we confirmed that the HIC1-CXCL14-CCL17 loop was associated with the malignant progression of BrCa. Therefore, the crosstalk between HIC1-deleted BrCa cells and mammary fibroblasts might play a critical role in BrCa development. Taken together, exploring the progression of BrCa from the perspective of microenvironment will be beneficial for identifying the potential prognostic marker of breast tumor and providing the more effective treatment strategy.

Recent advances have revealed the essential role of gut microbiomes in the therapeutic efficiency of immune checkpoint inhibitors (ICIs). Inspired by biostimulation, a method using nutrients to accelerate the growth of soil microorganisms and the recovery of soil microbial consortia, here we propose a bilberry anthocyanin combo containing chitosan and low molecular citrus pectin (LCP), in which LCP–chitosan is used to encapsulate anthocyanins so to enhance its digestive stability and, moreover, modulate the microbiome more favorable for the PD-L1 blockade treatment. Using murine MC38 colon cancer as a model system, we examined the effects of the combo on modulating the gut microbiome and therapeutic efficiency of PD-L1 blockade treatment. It was shown that bilberry anthocyanins enriched the subdominant species, increased both the concentration and the proportion of butyrate in feces and enhanced intratumoral CD8⁺ T cell infiltrations. The application of the bilberry anthocyanin combo restored the species diversity of gut microbiome decreased by LCP–chitosan and achieved the best control of tumor growth. These preliminary results indicated unprecedented opportunities of probiotics combo in improving the therapeutic efficiency of immune checkpoint inhibitor through manipulating gut microbiome.

The undesirable low response rate is a major hurdle to garnering the maximum potential of immune checkpoint inhibitors in cancer treatments. Recent advances in exploring the effects of intestinal flora on the medical efficacy of immune checkpoint blockade have shed new light on the application of immune checkpoint inhibitors. Inspired by the prebiotic role of anthocyanin-rich extracts, we propose using bilberry anthocyanin extracts to modulate the composition of gut microbiota and eventually, promote the efficiency of immune checkpoint inhibitors. This study demonstrates the effectiveness of orally administered bilberry anthocyanin extracts in enhancing the anti-tumor efficiency of the PD-L1 antibody in the experimental mouse MC38 tumor model. We observed an increase in the fecal abundance of Clostridia and Lactobacillus johnsonii and improved effective community diversity. These findings reinforce the importance of intestinal flora composition and open up unprecedented opportunities in using natural compounds to enhance the efficacy of immune checkpoint inhibitors.

Radiation-induced lung injury (RILI) is the main complication of radiotherapy for thoracic malignancies. Since naringenin, a potent immune-modulator, has been found to relieve bleomycin-induced lung fibrosis by restoring the balance of disordered cytokines, we sought to determine whether naringenin would mitigate RILI and to investigate the underlying mechanism. Animals received fractionated irradiation in the thoracic area to induce RILI. Enzyme-linked immunosorbent assay and MILLIPLEX assays were used for serum and bronchoalveolar lavage fluid for cytokine analyses, hematoxylin and eosin staining for pathologic changes, and Masson trichrome staining for determination of lung fibrosis. Interleukin (IL)-1β was found significantly elevated after thoracic irradiation and it triggered production of profibrotic tumor growth factor β both in vivo and in vitro, suggesting the vital role of in IL-1β in the development of RILI. Furthermore, we found that naringenin was able to ameliorate RILI through downregulation of IL-1β and restoration of the homeostasis of inflammatory factors. Our results demonstrated that naringenin could serve as a potent immune-modulator to ameliorate RILI. More importantly, we suggest that a new complementary strategy of maintaining the homeostasis of inflammatory factors combined with radiation could improve the efficacy of thoracic radiotherapy.