BackgroundThere is an urgent need for effective treatments for hepatocellular carcinoma (HCC). Immunotherapy is promising especially when combined with traditional therapies. This study aimed to investigate the immunomodulatory function of an approved Chinese medicine formula, compound kushen injection (CKI), and its anti-HCC efficiency in combination with low-dose sorafenib.MethodsGrowth of two murine HCC cells was evaluated in an orthotopic model, a subcutaneous model, two postsurgical recurrence model, and a tumor rechallenge model with CKI and low-dose sorafenib combination treatment. In vivo macrophage or CD8+T cell depletion and in vitro primary cell coculture models were used to determine the regulation of CKI on macrophages and CD8+T cells.ResultsCKI significantly enhanced the anticancer activity of sorafenib at a subclinical dose with no obvious side effects. CKI and sorafenib combination treatment prevented the postsurgical recurrence and rechallenged tumor growth. Further, we showed that CKI activated proinflammatory responses and relieved immunosuppression of tumor-associated macrophages in the HCC microenvironment by triggering tumor necrosis factor receptor superfamily member 1 (TNFR1)-mediated NF-κB and p38 MAPK signaling cascades. CKI-primed macrophages significantly promoted the proliferation and the cytotoxic ability of CD8+T cells and decreased the exhaustion, which subsequently resulted in apoptosis of HCC cells.ConclusionsCKI acts on macrophages and CD8+T cells to reshape the immune microenvironment of HCC, which improves the therapeutic outcomes of low-dose sorafenib and avoids adverse chemotherapy effects. Our study shows that traditional Chinese medicines with immunomodulatory properties can potentiate chemotherapeutic drugs and provide a promising approach for HCC treatment.

Titanium dioxide nanoparticles (TiO NPs) are widely used in foods, cosmetics, and medicine. Although the inhalation toxicity of TiO NPs has been studied, the potential adverse effects of oral exposure of low-dose TiO NPs are largely unclear. Herein, with macrophage cell lines, primary cells, and mouse models, we show that TiO NPs prime macrophages into a specific activation state characterized by excessive inflammation and suppressed innate immune function. After a month of dietary exposure in mice or exposure in vitro to TiO NPs (10 and 50 nm), the expressions of pro-inflammatory genes in macrophages were increased, and the expressions of anti-inflammatory genes were decreased. In addition, for macrophages exposed to TiO NPs in vitro and in vivo, their chemotactic, phagocytic, and bactericidal activities were lower. This imbalance in the immune system could enhance the susceptibility to infections. In mice, after a month of dietary exposure to low doses of TiO NPs, an aggravated septic shock occurred in response to lipopolysaccharide challenge, leading to elevated levels of inflammatory cytokines in serum and reduced overall survival. Moreover, TLR4-deficient mice and primary macrophages, or TLR4-independent stimuli, showed less response to TiO NPs. These results demonstrate that TiO NPs induce an abnormal state of macrophages characterized by excessive inflammation and suppressed innate immune function in a TLR4-dependent manner, which may suggest a potential health risk, particularly for those with additional complications, such as bacterial infections.

BackgroundThe clinical benefits of antiprogrammed cell death protein 1 (PD-1) therapy are compromised by resistance in immunologically cold tumors. Convergence of immunotherapy and bioengineering is potential to overcome the resistance. Mesoporous silica nanoparticles (MSNs) are considered the most promising inorganic biological nanomaterials for clinical transformation, however, the fundamental influence of MSNs on immunotherapy is unclear. In this study, we aimed to investigate the role of MSNs in tumor resensitization and explore the feasibility of MSNs combined with anti-PD-1 in cancer therapy.MethodsIntrinsic and acquired resistant tumors, as well as spontaneous and secondary tumor recurrence models, were used to evaluate the influence of MSNs and the synergistical effect with anti-PD-1 therapy. The roles of CD8+ cytotoxic T-lymphocytes (CTLs) and macrophages were assessed in Rag-1-/- mice, ovalbumin/OT-1 TCR transgenic T-cell system, and other blocking mice models. Mechanistic studies were processed by transcriptomics analysis and conducted in primary cells, in vitro coculture systems, and Toll-like receptor 4 (TLR4) knockout mice.ResultsBoth granular and rod-shaped MSNs efficiently overcame tumor resistance with dependence on diameter and aspect ratio. Only once injection of MSNs in prior to anti-PD-1 markedly improved the treatment efficacy, protective immunity, and prognosis. MSNs per se boosted infiltration of CTLs as the early event (days 2–3); and synergistically with anti-PD-1 therapy, MSNs rapidly established a T cell-inflamed microenvironment with abundant high-activated (interferon-γ/tumor necrosis factor-α/Perforin/GranzymeB) and low-exhausted (PD-1/lymphocyte-activation gene 3 (LAG-3)/T-cell immunoglobulin and mucin-domain containing-3 (TIM-3)) CTLs. Chemokines Ccl5/Cxcl9/Cxcl10, which were produced predominantly by macrophages, promoted MSNs-induced CTLs infiltration. MSNs led to high Ccl5/Cxcl9/Cxcl10 production in vitro and in mice through regulating TLR4-NFκB axis. Blocking TLR4-NFκB axis in macrophages or CTLs infiltration abrogated MSNs-induced resensitization to anti-PD-1 therapy.ConclusionsMSNs efficiently and rapidly inflame immunologically cold tumors and resensitize them to anti-PD-1 therapy through TLR4-NFκB-Ccl5/Cxcl9/Cxcl10 axis. MSNs-based theranostic agents can serve as sensitizers for patients with resistant tumors to improve immunotherapy.

1. CKI -suppresses liver fibrosis and hepatocarcinogenesis in both preclinical and clinical studies. 2. CKI inhibits HSCs activation by stabilizing the interaction of Smad7/TGFβR1 to rebalance Smad2/Smad3 signaling, acting as an alternative approach to target TGF-β signaling.3. High expression of Smad7 and low expression of TGFβR1 in HCC tumors and surrounding normal liver tissues can be tumor suppressive.

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Macrophages play a vital role in cardiac repair following myocardial infarction (MI). An enriched environment (EE) is involved in the regulation of macrophage-related activities and disease progression; however, whether EE affects the phenotype and function of macrophages to improve postinfarction cardiac repair remains unknown. In this study, we found that EE improved cardiac function, decreased mortality, and ameliorated adverse ventricular remodeling in mice after MI, with these outcomes closely related to the increased survival of Ly6C low macrophages and their CCR2 − MHCII low subsets. EE increased the expression of brain-derived neurotrophic factor (BDNF) in the hypothalamus, leading to higher circulating levels of BDNF, which, in turn, regulated the cardiac macrophages. BDNF bound to tropomyosin receptor kinase B to activate downstream ERK1/2 and AKT pathways, promoting macrophage survival. These findings demonstrate that EE optimizes postinfarction cardiac repair and highlights the significance of EE as a previously unidentified strategy for impeding adverse ventricular remodeling.

Graphical AbstractSchematic diagram of tumor-derived exosomes induced organotropism and immunosuppression.

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