Insufficient tumor accumulation and distribution of photosensitizers as well as low antitumor immunity severely restrict the therapeutic efficacy of photothermal therapy (PTT). Cancer-associated ...fibroblasts (CAFs) play a key role in tumor extracellular matrix (ECM) remodeling and immune evasion. Reshaping tumor microenvironment via CAF regulation might provide a potential approach for complete tumor elimination in combination with PTT. Here, tumor cell-derived microparticles co-delivering calcipotriol and Indocyanine green (Cal/ICG@MPs) are developed to modulate CAFs for improved PTT efficacy. Cal/ICG@MPs efficiently target tumor tissues and regulate CAFs to reduce tumor ECM, resulting in enhanced tumor accumulation and penetration of ICG to generate strong PTT efficacy and activate CD8
T cell-mediated antitumor immunity. In addition, Cal/ICG@MPs-triggered CAF regulation enhances tumor infiltration of CD8
T cells and ameliorates CAF-induced antigen-mediated activation-induced cell death of tumor-specific CD8
T cells in response to PTT, eliciting long-term antitumor immune memory to inhibit tumor recurrence and metastasis. Our results support Cal/ICG@MPs as a promising drug to improve PTT efficacy in cancer treatment.
The main challenges for programmed cell death 1(PD-1)/PD-1 ligand (PD-L1) checkpoint blockade lie in a lack of sufficient T cell infiltration, tumor immunosuppressive microenvironment, and the ...inadequate tumor accumulation and penetration of anti-PD-1/PD-L1 antibody. Resetting tumor-associated macrophages (TAMs) is a promising strategy to enhance T-cell antitumor immunity and ameliorate tumor immunosuppression. Here, mannose-modified macrophage-derived microparticles (Man-MPs) loading metformin (Met@Man-MPs) are developed to efficiently target to M2-like TAMs to repolarize into M1-like phenotype. Met@Man-MPs-reset TAMs remodel the tumor immune microenvironment by increasing the recruitment of CD8
T cells into tumor tissues and decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and regulatory T cells. More importantly, the collagen-degrading capacity of Man-MPs contributes to the infiltration of CD8
T cells into tumor interiors and enhances tumor accumulation and penetration of anti-PD-1 antibody. These unique features of Met@Man-MPs contribute to boost anti-PD-1 antibody therapy, improving anticancer efficacy and long-term memory immunity after combination treatment. Our results support Met@Man-MPs as a potential drug to improve tumor resistance to anti-PD-1 therapy.
Developing biomimetic nanoparticles without loss of the integrity of proteins remains a major challenge in cancer chemotherapy. Here, we develop a biocompatible tumor-cell-exocytosed ...exosome-biomimetic porous silicon nanoparticles (PSiNPs) as drug carrier for targeted cancer chemotherapy. Exosome-sheathed doxorubicin-loaded PSiNPs (DOX@E-PSiNPs), generated by exocytosis of the endocytosed DOX-loaded PSiNPs from tumor cells, exhibit enhanced tumor accumulation, extravasation from blood vessels and penetration into deep tumor parenchyma following intravenous administration. In addition, DOX@E-PSiNPs, regardless of their origin, possess significant cellular uptake and cytotoxicity in both bulk cancer cells and cancer stem cells (CSCs). These properties endow DOX@E-PSiNPs with great in vivo enrichment in total tumor cells and side population cells with features of CSCs, resulting in anticancer activity and CSCs reduction in subcutaneous, orthotopic and metastatic tumor models. These results provide a proof-of-concept for the use of exosome-biomimetic nanoparticles exocytosed from tumor cells as a promising drug carrier for efficient cancer chemotherapy.
Extracellular microparticles (MPs) can function as drug-delivery vehicles for anticancer drugs. Here, we show that the softness of MPs derived from tumour-repopulating cells (TRCs) isolated from ...three-dimensional fibrin gels enhances the MPs' drug-delivery efficiency. We found that, compared with MPs derived from tumour cells cultured in conventional tissue-culture plastic, TRC-derived MPs intravenously injected in tumour-xenograft-bearing mice showed enhanced accumulation in tumour tissues, enhanced blood-vessel crossing and penetration into tumour parenchyma, and preferential uptake by highly tumorigenic TRCs. We also show that the cytoskeleton-related protein cytospin-A plays a critical role in the regulation of TRC-derived MP softness. The modulation of the mechanical properties of TRC-derived MPs could aid the efficiency of delivery of anticancer drugs.
The therapeutic efficacy of programmed cell death protein 1/programmed cell death-ligand 1 (PD-1/PD-L1) blockade immunotherapy is extremely dampened by complex immunosuppressive mechanisms including ...regulatory T cells (Treg), M2 macrophages (M2), and prostaglandin E2 (PGE2). The pivotal roles of PGE2 have been recognized by directly inactivating CD8+ T cells and indirectly inducing Treg and M2. Therefore, PGE2 abolishment through inactivating cyclooxygenase-2 (COX-2) could be robust to sensitize tumour toward anti-PD-1/PD-L1 immunotherapy, which has gone into clinical trials. However, exploring this promising strategy in nanomedicine to enhance immunotherapy remains unrevealed. The key challenge to synergistically combine COX-2 inhibition and anti-PD-1/PD-L1 lies in the different pharmacokinetic profiles and the spatial obstacles since PD-1/PD-L1 interaction occurs extracellularly and COX-2 locates intracellularly. Thus, the programmed release nanoparticles (termed as Cele-BMS-NPs) are rationally designed, which are composed of pH-sensitive human serum albumin derivative, BMS-202 compound as PD-1/PD-L1 inhibitor, glutathione (GSH)-activatable prodrug of celecoxib (COX-2 inhibitor). The
in vitro
experiments demonstrate that this smart Cele-BMS-NPs could extracellularly release BMS-202 under the acidic tumour microenvironment, and the intracellularly release of celecoxib in response to the elevated GSH concentration inside tumour cells. After systemic administration, the intratumoral infiltration of CD8+ T cells is significantly enhanced and meanwhile immunosuppressive M2, Treg, and PGE2 are reduced, thereby eliciting the anti-tumour immune responses toward low immunogenic tumours and postsurgical tumour recurrences.
Abstract
The durable response rate to immune checkpoint blockade such as anti-programmed cell death-1 (PD-1) antibody remains relatively low in hepatocellular carcinoma (HCC), mainly depending on an ...immunosuppressive microenvironment with limited number of CD8
+
T cells, especially stem-like CD8
+
T cells, in tumor tissues. Here we develop engineered microparticles (MPs) derived from alpha-fetoprotein (AFP)-overexpressing macrophages to load resiquimod (R848@M2pep-MPs
AFP
) for enhanced anti-PD-1 therapy in HCC. R848@M2pep-MPs
AFP
target and reprogram immunosuppressive M2-like tumor-associated macrophages (TAMs) into M1-like phenotype. Meanwhile, R848@M2pep-MPs
AFP
-reprogrammed TAMs act as antigen-presenting cells, not only presenting AFP antigen to activate CD8
+
T cell-mediated antitumor immunity, but also providing an intra-tumoral niche to maintain and differentiate stem-like CD8
+
T cells. Combination immunotherapy with anti-PD-1 antibody generates strong antitumor immune memory and induces abundant stem-like CD8
+
T cell proliferation and differentiation to terminally exhausted CD8
+
T cells for long-term immune surveillance in orthotopic and autochthonous HCC preclinical models in male mice. We also show that the R848-loaded engineered MPs derived from macrophages overexpressing a model antigen ovalbumin (OVA) can improve anti-PD-1 therapy in melanoma B16-OVA tumor-bearing mice. Our work presents a facile and generic strategy for personalized cancer immunotherapy to boost anti-PD-1 therapy.
DHA can regulate various physiological functions of cells. Our group has clarified the immunomodulatory activity and molecular mechanism of DHA on RAW264.7 cells. However, the effect of DHA on the ...membrane fatty acid environment and the activation of signaling pathways on the cell membrane is still not clear.
In this study, we evaluated the fluidity, the potential and the fatty acid, phospholipid and protein composition of the RAW264.7 cell membrane by DHA treatment.
The fluidity of the RAW264.7 cell membrane was increased by DHA treatment. The results of membrane potential analysis suggested that DHA (2.4 μM) significantly reduced the surface potential of the cell membrane, which might influence the fluidity of cell membranes. In addition, the fatty acids and phospholipids were measured and the results indicated that DHA treatment (2.4 μM) altered the lipid environment and the composition of phospholipids on the RAW264.7 cell membrane. Then the LC-MS/MS-based label free quantitative proteomics approach was applied to identify a total of 86 differential proteins in the 2.4 μM DHA and control groups (>2.0-fold change or <0.5-fold change in protein expression); these proteins are most frequently related to the cell response to stimuli and the response to stress. These results suggested that DHA could alter the fluidity, the potential, the fatty acid and phospholipid composition of the RAW264.7 cell membrane, eventually affecting the proteins of the cell membrane, especially the changes in Siglec 1, iNOS, GPR120, Ras and MEK expressions (validated by western blot analysis), which are likely associated with the activation of the intracellular signaling pathway in RAW264.7 cells by DHA treatment.
Docosahexaenoic acid (DHA) has attracted plenty of interest in the prevention of neurodegenerative diseases. Although the beneficial effects of DHA on the central nervous system function are ...recognized, more information on the molecular mechanisms involved in its neuroprotective effects is required. The present study aimed to evaluate the effects of DHA on the function of mitochondria, neurite growth-related proteins signaling pathway, and neural signal transmission. In this study, PC12 cells were treated with H2O2 (400 μM) to establish an oxidative damage model. Results showed that DHA improved the viability and morphology of PC12 cells. DHA significantly increased the antioxidant capacity, mitochondrial membrane potential, and activity of ATPase in the cells. Furthermore, the phosphorylation levels of tyrosine kinase receptor (BTrkB), phospholipase C-γ1 (PLCγ1), calcium/calmodulin-dependent protein kinase II (CaMKII), extracellular regulated protein kinases 1/2 (ERK1/2), and cAMP-response element-binding protein (CREB) were upregulated by DHA. The damage on F-actin induced by H2O2 was reversed by DHA, indicating that DHA could protect neurite outgrowth. In addition, DHA increased the content of acetylcholine and γ-aminobutyric acid while decreasing glutamic acid. These results revealed that DHA could protect PC12 cells from damage induced by H2O2 through the TrkB-ERK1/2-CREB pathway.
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•EPA could attenuate ovarian cancer by improving the immunomodulatory.•EPA could increase the index of spleens and thymus and phagocytosis activity of macrophages.•The ...immunomodulatory effects of EPA were associated with PI3K/Akt, ERK1/2 and NF-κB P65 expression.
Eicosapentaenoic acid (EPA) has been known to induce human ovarian cancer cells apoptosis in vitro. However, the anti-tumor mechanisms of EPA in vivo have been rarely reported. In this study, the effect of EPA on the ovarian cancer rat model and its related mechanism were investigated. The results showed after EPA treatment, the index of spleens and thymus was significantly increased, and the proliferation of spleen cells, the natural killer (NK) cell activity and phagocytosis activity of macrophages were prompted. Besides, EPA could reverse the decrease of CD4+ and CD8+ T lymphocytes induced by ovarian cancer. It was found that EPA could inhibit the phosphorylation status of PI3K (phosphatidylinositol 3-hydroxy kinase)/Akt (serine-threonine kinase), ERK1/2 (extracellular signal-regulated kinase 1/2) and NF-κB p65, and prompt the expression of cytochrome C and caspase-3. These results suggested that EPA has a remarkable anti-tumor activity by improving the immunomodulatory on the ovarian cancer rat model.
Immune checkpoint blockade (ICB) therapy, particularly antibodies targeting the programmed death receptor 1 (PD-1) and its ligand (PD-L1), has revolutionized cancer treatment. However, its efficacy ...as a standalone therapy remains limited. Although ICB therapy in combination with chemotherapy shows promising therapeutic responses, the challenge lies in amplifying chemotherapy-induced antitumor immunity effectively. This relies on efficient drug delivery to tumor cells and robust antigen presentation by dendritic cells (DCs). Here, we developed tumor-repopulating cell (TRC)-derived microparticles with exceptional tumor targeting to deliver doxorubicin (DOX@3D-MPs) for improve anti-PD-1 therapy. DOX@3D-MPs effectively elicit immunogenic tumor cell death to release sufficient tumor antigens. Heat shock protein 70 (HSP70) overexpressed in DOX@3D-MPs contributes to capturing tumor antigens, promoting their phagocytosis by DCs, and facilitating DCs maturation, leading to the activation of CD8+ T cells. DOX@3D-MPs significantly enhance the curative response of anti-PD-1 treatment in large subcutaneous H22 hepatoma, orthotopic 4T1 breast tumor and Panc02 pancreatic tumor models. These results demonstrate that DOX@3D-MPs hold promise as agents to improve the response rate to ICB therapy and generate long-lasting immune memory to prevent tumor relapse.
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