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Lack of sufficient cytotoxic T lymphocytes (CD8+ T cells) infiltration and dysfunctional state of CD8+ T cells are considered enormous obstacles to antitumor immunity. Herein, we construct a synergistic nanoplatform to promote CD8+ T cell infiltration in tumors while restoring T cell function by regulating methionine metabolism and activating the STING innate immune pathway. The CRISPR/Cas9 system down-regulates the methionine transporter SLC43A2 and restricts the methionine uptake by tumor cells, thereby relieving the methionine competition pressure of T cells; simultaneously, the released nutrition metal ions activate the cGAS/STING pathway. In this work, the described nanoplatform can enhance the effect of immunotherapy in preclinical cancer models in female mice, enhancing STING pathway mediated immunity and facilitating the development of amino acid metabolic intervention-based cancer therapy. Metabolic pressure, in particular the lack of methionine availability, on tumor-infiltrating CD8 + T cells is associated with T cell dysfunction. Since tumor cells rely on SLC43A2 for methionine uptake, here the authors design a nanoplatform for CRISPR/Cas9 mediated silencing of SLC43A2 and STING activation, restoring anti-tumor T cell immune responses. [ABSTRACT FROM AUTHOR]

Metabolic glycan labeling (MGL) followed by bioorthogonal chemistry provides a powerful tool for tumor imaging and therapy. However, selectively metabolic labeling of cells or tissues of interest remains a challenge. Particularly, owing to tumor heterogeneity including tumor subtypes and interpatient heterogeneity, it is far more difficult to realize tumor‐cell‐selective metabolic labeling for precise diagnosis. Inspired by nature, we designed azidosugar‐functionalized metal–organic frameworks camouflaged with cancer cell membranes to accomplish cancer‐cell‐selective MGL in vivo. With abundant receptors, this biomimetic platform not only selectively targets homotypic cells but also realizes different breast cancer subtype‐selective MGL. Moreover, the endo/lysosomal‐escaped ZIF‐8 can make azidosugar escape from lysosomes and accelerate its metabolic incorporation. This strategy also takes advantage of cancer‐tissue‐derived cell membranes, which may have huge potential for personalized diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Silibinin, a nontoxic bioactive component in milk thistle, is used as a liver-protective drug in the clinic mainly because of its antioxidant and anti-inflammation activities. In this study, we studied the cytotoxic effects of silibinin combined with sorafenib on hepatocellular carcinoma (HCC). The results indicated that silibinin combined with sorafenib potently inhibited the proliferation of various HCC cells and induced significant apoptosis. In an HCC subcutaneous transplantation tumor model, the combination of silibinin and sorafenib significantly suppressed tumor growth compared with monotherapy. As determined by fluorescence staining and Western blots, the combination of the two drugs inhibited the phosphorylation of RAC-alpha serine/threonine-protein kinase (AKT) and signal transducer and activator of transcription 3 (STAT3) together with the expression of antiapoptotic proteins including myeloid leukemia cell differentiation protein Mcl-1 (Mcl-1) and apoptosis regulator Bcl-2 (Bcl-2), resulting in the death of cancer cells. We also found that the combination inhibited the formation and self-renewal of HCC stem cells by down-regulating the expression of stemness-related proteins, such as Homeobox protein NANOG (Nanog) and Krueppel-like factor 4 (Klf4). These results suggested that silibinin improved the efficacy of sorafenib in HCC therapy, indicating a clinical promising therapeutic strategy for HCC patients. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT), which employs intracellular H 2 O 2 to produce toxic hydroxyl radicals to kill cancer cells, has received great attention due to its specificity to tumors. However, the relatively insufficient endogenous H 2 O 2 and the short-lifetime and limited diffusion distance of •OH compromise the therapeutic efficacy of CDT. Mitochondria, which play crucial roles in oncogenesis, are highly vulnerable to elevated oxidative stress. Herein, we constructed a mitochondria-mediated self-cycling system to achieve high dose of •OH production through continuous H 2 O 2 supply. Cinnamaldehyde (CA), which can elevate H 2 O 2 level in the mitochondria, was loaded in Cu(II)-containing metal organic framework (MOF), termed as HKUST-1. After actively targeting mitochondria, the intrinsic H 2 O 2 in mitochondria of cancer cells could induce degradation of MOF, releasing the initial free CA. The released CA further triggered the upregulation of endogenous H 2 O 2 , resulting in the subsequent adequate release of CA and the final burst growth of H 2 O 2. The cycle process greatly promoted the Fenton-like reaction between Cu2+ and H 2 O 2 and induced long-term high oxidative stress, achieving enhanced chemodynamic therapy. In a word, we put forward an efficient strategy for enhanced chemodynamic therapy. • A mitochondria-specific nanoreactor is constructed for chemodynamic therapy. • The self-cycling nanoreactor enables continuous supply of H 2 O 2 to produce ROS. • The uninterrupted oxidative damage of mitochondria achieves enhanced efficiency. [ABSTRACT FROM AUTHOR]