Cuproptosis is a newly discovered copper ion‐dependent programmed cell death. Elesclomol (ES) is a Cu²⁺ transporter that delivers Cu²⁺ into tumor cells, causing cell death at toxic doses. However, ES has a short blood half‐life, limiting its accumulation in tumors. This study introduces Tussah silk fibroin nanoparticles (TSF@ES‐Cu NPs) to protect ES and Cu²⁺. TSF, with a stable structure, resists metabolism in circulation. Targeting tumors with natural RGD peptides and TSF's unique secondary structure, enhances drug enrichment and special release in pancreatic tumors, improving treatment efficacy. In vitro, TSF@ES‐Cu induces tumor cell cuproptosis, releases DAMPs, promotes dendritic cells (DCs) maturation, and macrophage M1 polarization. In vivo, TSF@ES‐Cu reshapes the tumor microenvironment (TME), increasing mature DCs from 22.7% to 43.3%, CD8⁺ T cells from 5.08% to 17.1%, and reducing M2 macrophages from 50.7% to 18.4%. Additionally, the combined anti‐tumor efficacy of TSF@ES‐Cu and αPDL‐1 is 1.6 times higher than TSF@ES‐Cu alone and 2.5 times higher than αPDL‐1 alone. In summary, this study reports that the combination of TSF@ES‐Cu and αPDL‐1 effectively induces cuproptosis and reshapes the TME, offering a new approach for copper nanomaterial‐based tumor immunotherapy.

Family with sequence similarity 96 member A (FAM96A) is an evolutionarily conserved intracellular protein that is involved in the maturation of the Fe/S protein, iron regulatory protein 1 (IRP1), and the mitochondria-related apoptosis of gastrointestinal stromal tumor cells. In this study, we used a mouse model of chemically induced colitis to investigate the physiological role of FAM96A in intestinal homeostasis and inflammation. At baseline, colons from Fam96a^−/− mice exhibited microbial dysbiosis, dysregulated epithelial cell turnover, an increased number of goblet cells, and disordered tight junctions with functional deficits affecting intestinal permeability. After cohousing, the differences between wild-type and Fam96a^−/− colons were abrogated, suggesting that FAM96A affects colonic epithelial cells in a microbiota-dependent manner. Fam96a deficiency in mice resulted in increased susceptibility to dextran sulfate sodium (DSS)-induced colitis. Importantly, the colitogenic activity of Fam96a^−/− intestinal microbiota was transferable to wild-type littermate mice via fecal microbial transplantation (FMT), leading to exacerbation of DSS-induced colitis. Taken together, our data indicate that FAM96A helps to maintain colonic homeostasis and protect against DSS-induced colitis by preventing gut microbial dysbiosis. This study used gene knockout animals to help to understand the in vivo effects of the Fam96a gene for the first time and provides new evidence regarding host–microbiota interactions.

C1q/TNF-related protein 4 (CTRP4) is generally thought to be released extracellularly and plays a critical role in energy metabolism and protecting against sepsis. However, its physiological functions in autoimmune diseases have not been thoroughly explored. In this study, we demonstrate that Th17 cell–associated experimental autoimmune encephalomyelitis was greatly exacerbated in Ctrp4^–/– mice compared with WT mice due to increased Th17 cell infiltration. The absence of Ctrp4 promoted the differentiation of naive CD4⁺ T cells into Th17 cells in vitro. Mechanistically, CTRP4 interfered with the interaction between IL-6 and the IL-6 receptor (IL-6R) by directly competing to bind with IL-6R, leading to suppression of IL-6–induced activation of the STAT3 pathway. Furthermore, the administration of recombinant CTRP4 protein ameliorated disease symptoms. In conclusion, our results indicate that CTRP4, as an endogenous regulator of the IL-6 receptor–signaling pathway, may be a potential therapeutic intervention for Th17-driven autoimmune diseases.