Engineered bacteria in tumor immunotherapy.

As the limitations of cancer immunotherapy become increasingly apparent, there is considerable anticipation regarding the utilization of biological tools to enhance treatment efficacy, particularly bacteria and their derivatives. Leveraging advances in genetic and synthetic biology technologies, engineered bacteria now play important roles far beyond those of conventional immunoregulatory agents, and they could function as tumor-targeting vehicles and in situ pharmaceutical factories. In recent years, these engineered bacteria play a role in almost every aspect of immunotherapy. It is nothing short of impressive to keep seeing different strain of bacteria modified in diverse ways for unique immunological enhancement. In this review, we have scrutinized the intricate interplay between the immune system and these engineered bacteria. These interactions generate strategies that can directly or indirectly optimize immunotherapy and even modulate the effects of combination therapies. Collectively, these engineered bacteria present a promising novel therapeutic strategy that promises to change the current landscape of immunotherapy.

Nanozyme-Coated Bacteria Hitchhike on CD11b+ Immune Cells to Boost Tumor Radioimmunotherapy.

Bacterial-based delivery strategies have recently emerged as a unique research direction in the field of drug delivery. However, bacterial vectors are quickly phagocytosed by immune cells after entering the bloodstream. Taking advantage of this phenomenon, herein, this work seeks to harness the potential of immune cells to delivery micron-sized bacterial vectors, and find that inactivated bacterial can accumulate at tumor-site after intravenous injection through CD11b+ cells hitchhiking. To this end, this work then designs a gold-platinum bimetallic nanozyme coated bacterial vector (Au-Pt@VNP20009, APV). Utilizing strong tumor inflammatory response induced by low dose X-rays, this work further heightens the ability of CD11b+ immune cells to assist APV hitchhiking for tumor-targeted delivery, which can significantly relieve tumor hypoxia and immunosuppression, and inhibit tumor growth and metastasis. This work elucidates the potential mechanisms of bacterial vector targeted delivery, opening up new horizons for bacterial vector delivery strategies and clinical tumor radioimmunotherapy.

A Polymeric Hydrogel to Eliminate Programmed Death-Ligand 1 for Enhanced Tumor Radio-Immunotherapy.

Programmed death-ligand 1 (PD-L1) is a specialized shield on tumor cells that evades the immune system. Even inhibited by PD-L1 antibodies, a cycling process constantly transports PD-L1 from inside to outside of cells, facilitating the renewal and replenishment of PD-L1 on the cancer cell membrane. Herein, we develop a sodium alginate hydrogel consisting of elesclomol-Cu and galactose to induce persistent cuproptosis, leading to the reduction of PD-L1 for radio-immunotherapy of colon tumors. First, a prefabricated hydrogel is synthesized by immobilizing elesclomol onto a sodium alginate saccharide chain through the coordination with bivalent copper ions (Cu2+), followed by incorporation of galactose. After implantation into the tumors, this prefabricated hydrogel can be further cross-linked in the presence of physiological calcium ions (Ca2+), resulting in the formation of a hydrogel with controlled release of elesclomol-Cu2+ (ES-Cu) and galactose. The hydrogel effectively induces the oligomerization of DLAT and cuproptosis in colorectal cancer cells. Interestingly, radiation-induced PD-L1 upregulation is abrogated in the presence of the hydrogel, releasing ES-Cu and galactose. Consequently, the sensitization of tumor to radiotherapy and immunotherapy is significantly improved, further prolonging the survival of tumor-bearing mice in both local and metastatic tumors. Our study introduces an approach that combines cuproptosis with immunotherapy and radiotherapy.

WITHDRAWN: Identification of abnormally expressed genes and their roles in invasion and migration of hepatocellular carcinoma.

This paper was originally published in Aging Advance Online Publications on February 2, 2020. In compliance with Aging's withdrawal policy, the paper was withdrawn in its entirety. It will not appear in Aging internal or any external indexes or archives.

BDE-209 induces male reproductive toxicity via cell cycle arrest and apoptosis mediated by DNA damage response signaling pathways.

Decabromodiphenyl ether (BDE-209) is commonly used as a flame retardant, usually in products that were utilized in electronic equipment, plastics, furniture and textiles. To identify the impacts of BDE-209 on the male reproductive system and the underlying toxicological mechanisms, 40 male ICR mice were randomly divided into four groups, which were then exposed to BDE-209 at 0, 7.5, 25 and 75 mg kg-1 d-1 for four weeks, respectively. With regard to the in vitro study, GC-2spd cells were treated with BDE-209 at 0, 2, 8 and 32 µg mL-1 for 24 h, respectively. The results from the in vivo experiments showed that BDE-209 resulted in damage to the testis structure, led to cell apoptosis in testis and decreased sperm number and motility, while sperm malformation rates were significantly increased. Moreover, BDE-209 could induce oxidative stress with decreased testosterone levels, result in DNA damage and activate DNA damage response signaling pathways (ATM/Chk2, ATR/Chk1 and DNA-PKcs/XRCC4/DNA ligase Ⅳ). The data from the in vitro experiments showed that BDE-209 led to cytotoxicity by reducing cell viability and increasing LDH release as well. BDE-209 also induced DNA strand breaks, cell cycle arrest at G1 phase and elevated reactive oxygen species (ROS) level in GC-2 cells. These results suggested that BDE-209 could lead to male reproductive toxicity by inducing DNA damage and failure of DNA damage repair which resulted in cell cycle arrest and apoptosis of spermatogenic cell. The present study provided new evidence to elucidate the potential mechanism of male reproductive toxicity induced by BDE-209.