Despite the widespread applications of manganese oxide nanomaterials (MONs) in biomedicine, the intrinsic immunogenicity of MONs is still unclear. MnOx nanospikes (NSs) as tumor microenvironment (TME)‐responsive nanoadjuvants and immunogenic cell death (ICD) drugs are proposed for cancer nanovaccine‐based immunotherapy. MnOx NSs with large mesoporous structures show ultrahigh loading efficiencies for ovalbumin and tumor cell fragment. The combination of ICD via chemodynamic therapy and ferroptosis inductions, as well as antigen stimulations, presents a better synergistic immunopotentiation action. Furthermore, the obtained nanovaccines achieve TME‐responsive magnetic resonance/photoacoustic dual‐mode imaging contrasts, while effectively inhibiting primary/distal tumor growth and tumor metastasis.

Despite the comprehensive applications in bioimaging, biosensing, drug/gene delivery, and tumor therapy of manganese oxide nanomaterials (MONs including MnO2, MnO, Mn2O3, Mn3O4, and MnOx) and their derivatives, a review article focusing on MON‐based nanoplatforms has not been reported yet. Herein, the representative progresses of MONs on synthesis, heterogene, properties, surface modification, toxicity, imaging, biodetection, and therapy are mainly introduced. First, five kinds of primary synthetic methods of MONs are presented, including thermal decomposition method, exfoliation strategy, permanganates reduction method, adsorption–oxidation method, and hydro/solvothermal. Second, the preparations of hollow MONs and MON‐based composite materials are summarized specially. Then, the chemical properties, surface modification, and toxicity of MONs are discussed. Next, the diagnostic applications including imaging and sensing are outlined. Finally, some representative rational designs of MONs in photodynamic therapy, photothermal therapy, chemodynamic therapy, sonodynamic therapy, radiotherapy, magnetic hyperthermia, chemotherapy, gene therapy, starvation therapy, ferroptosis, immunotherapy, and various combination therapy are highlighted.

Control of inflammation is critical for therapy of infectious diseases. Pathogen-associated and/or danger-associated molecular patterns (PAMPs and DAMPs, respectively) are the two major inducers of inflammation. Because the CD24-Siglec G/10 interactions selectively repress inflammatory response to DAMPs, microbial disruption of the negative regulation would provide a general mechanism to exacerbate inflammation. Here we show that the sialic acid-based pattern recognitions of CD24 by Siglec G/10 are targeted by sialidases in polybacterial sepsis. Sialidase inhibitors protect mice against sepsis by a CD24-Siglecg-dependent mechanism, whereas a targeted mutation of either CD24 or Siglecg exacerbates sepsis. Bacterial sialidase and host CD24 and Siglecg genes interact to determine pathogen virulence. Our data demonstrate a critical role for disrupting sialic acid-based pattern recognitions in microbial virulence and suggest a therapeutic approach to dampen harmful inflammatory response during infection.

Immunogenic cell death (ICD), a manner of tumor cell death that can trigger antitumor immune responses, has received extensive attention as a potential synergistic modality for cancer immunotherapy. Although many calcium ion (Ca 2+ ) nanomodulators have been developed for cancer therapy through mitochondrial Ca 2+ overload, their ICD-inducing properties have not been explored. Herein, an acid-sensitive PEG-decorated calcium carbonate (CaCO 3 ) nanoparticle incorporating curcumin (CUR; a Ca 2+ enhancer) ( PEG CaCUR) was prepared using a simple one-pot strategy. PEG CaCUR served as not only a Ca 2+ nanomodulator inducing efficient mitochondrial Ca 2+ overload but also an ICD inducer during improved synergistic cancer therapy. Combination of PEG CaCUR with ultrasound (US), PEG CaCUR+US, led to an enhanced ICD effect attributable to the enhanced mitochondrial Ca 2+ overload, along with subsequent upregulation of reactive oxygen species levels. PEG CaCUR also facilitates photoacoustic/fluorescence dual-mode imaging, as well as effectively suppressing tumor growth and metastasis, indicating promising theranostic properties.

Versican/PG-M is an extracellular matrix proteoglycan, expression of which is elevated in a variety of human tumors. The significance of this change is unclear. Here we show that versican G3-containing fragments are present at high levels in human astrocytoma. Expression of a versican G3 construct in U87 astrocytoma cells enhances colony growth in soft agarose gel and tumor growth and blood vessel formation in nude mice. The G3-containing medium enhances endothelial cell adhesion, proliferation, and migration. G3-expressing cells and tumors formed by these cells express increased levels of fibronectin and vascular endothelial growth factor (VEGF). Furthermore, the G3 domain directly binds to fibronectin and forms a complex together with VEGF. In the presence of these three molecules, endothelial cell adhesion, proliferation, and migration were found to be significantly enhanced. Removal of the complex containing these molecules reverses these processes. Taken together, these findings implicate G3 as a modifier of tumor growth and angiogenesis and suggest a new avenue for development of anticancer and anti-angiogenic therapies based on targeting versican G3 fragments.

Subcellular organelle‐targeted nanoformulations for cancer theranostics are receiving increasing attention owing to their benefits of precise drug delivery, maximized therapeutic index, and reduced off‐target side effects. Herein, a multichannel calcium ion (Ca2+) nanomodulator (CaNMCUR+CDDP), i.e., a cisplatin (CDDP) and curcumin (CUR) co‐incorporating calcium carbonate (CaCO3) nanoparticle, is prepared by a facile one‐pot strategy in a sealed container with in situ synthesized polydopamine (PDA) as a template to enhance Ca2+‐overload‐induced mitochondrial dysfunction in cancer therapy. After systemic administration, the PEGylated CaNMCUR+CDDP (PEGCaNMCUR+CDDP) selectively accumulates in tumor tissues, enters tumor cells, and induces multilevel destruction of mitochondria by the combined effects of burst Ca2+ release, Ca2+ efflux inhibition by CUR, and chemotherapeutic CDDP, thereby observably boosting mitochondria‐targeted tumor inhibition. Fluorescence imaging of CUR combined with photoacoustic imaging of PDA facilitates the visualization of the nanomodulator. The facile and practical design of this multichannel Ca2+ nanomodulator will contribute to the development of multimodal bioimaging‐guided organelle‐targeted cancer therapy in the future.

Treg play a central role in maintenance of self tolerance and homeostasis through suppression of self-reactive T cell populations. In addition to that role, Treg also survey cancers and suppress anti-tumor immune responses. Thus, understanding the unique attributes of Treg-tumor interactions may permit control of this pathologic suppression without interfering with homeostatic self-tolerance. This review will define the unique role of Treg in cancer growth, and the ways by which Treg inhibit a robust anti-tumor immune response. There will be specific focus placed on Treg homing to the tumor microenvironment (TME), TME formation of induced Treg (iTreg), mechanisms of suppression that underpin cancer immune escape, and trophic nonimmunologic effects of Treg on tumor cells.

BackgroundGrowth differentiation factor 15 (GDF15) is a member of the TGF-β superfamily, and evidence suggests that a substantial amount of GDF15 is secreted in various human cancers, such as ovarian cancer, prostate cancer, and breast cancer, among others. However, the function of GDF15 in cervical cancer has not yet been reported.MethodsImmunohistochemistry was used to detect GDF15 expression in normal cervix and in different cervical cancer lesions. Cell growth curves, MTT, tumor formation assays and flow cytometry were utilized to observe the effects of ectopic GDF15 expression on the proliferation and cell cycle of cervical cancer cells. Real-time PCR, western blotting and immunoprecipitation assays were conducted to measure the expression of genes related to the cell cycle and the PI3K/AKT and MAPK/ERK signaling pathways. A chromatin immunoprecipitation assay was performed to confirm whether C-myc bound to a specific region of the GDF15 promoter. Inhibitor treatment and immunoprecipitation assays were employed to identify the association between GDF15 and ErbB2.ResultsGDF15 expression gradually increased during the progression of cervical carcinogenesis. GDF15 promoted cervical cancer cell proliferation via exogenous rhGDF15 treatment or the use of gene editing technology in vitro and in vivo and significantly accelerated the cell cycle transition from G0/G1 to S phase. The expression of p-ErbB2, p-AKT1, p-Erk1/2, CyclinD1 and CyclinE1 was up-regulated and the expression of p21 was down-regulated in GDF15-overexpressing and rhGDF15-treated cervical cancer cells. C-myc trans-activated GDF15 expression by binding to the E-box motifs in the promoter of GDF15 and contributed to the positive feedback of GDF15/C-myc/GDF15. Furthermore, GDF15 bound to ErbB2 in a protein complex in cervical cancer cells.ConclusionsOur data demonstrated that GDF15 promoted the proliferation of cervical cancer cells via the up-regulation of CyclinD1 and CyclinE1 and the down-regulation of p21 through both the PI3K/AKT and MAPK/ERK signaling pathways in a complex with ErbB2.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0744-0) contains supplementary material, which is available to authorized users.