Endometriosis, affecting 6%-10% of women, often leads to pain and infertility and its underlying inflammatory mechanisms are poorly understood. We established endometriosis models in wild-type and IL16KO mice, revealing the driver function of IL-16 in initiating endometriosis-related inflammation. Using an in vitro system, we confirmed iron overload-induced GSDME-mediated pyroptosis as a key trigger for IL-16 activation and release. In addition, our research led to the development of Z30702029, a compound inhibiting GSDME-NTD-mediated pyroptosis, which shows promise as a therapeutic intervention for endometriosis. Importantly, our findings extend beyond endometriosis, highlighting GSDME-mediated pyroptosis as a broader pathway for IL-16 release and offering insights into potential treatments for various inflammatory conditions.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable success in the treatment of hematologic malignancies. Unfortunately, it has limited efficacy against solid tumors, even when the targeted antigens are well expressed. A better understanding of the underlying mechanisms of CAR T-cell therapy resistance in solid tumors is necessary to develop strategies to improve efficacy. Here we report that solid tumors release small extracellular vesicles (sEV) that carry both targeted tumor antigens and the immune checkpoint protein PD-L1. These sEVs acted as cell-free functional units to preferentially interact with cognate CAR T cells and efficiently inhibited their proliferation, migration, and function. In syngeneic mouse tumor models, blocking tumor sEV secretion not only boosted the infiltration and antitumor activity of CAR T cells but also improved endogenous antitumor immunity. These results suggest that solid tumors use sEVs as an active defense mechanism to resist CAR T cells and implicate tumor sEVs as a potential therapeutic target to optimize CAR T-cell therapy against solid tumors.
Small extracellular vesicles secreted by solid tumors inhibit CAR T cells, which provide a molecular explanation for CAR T-cell resistance and suggests that strategies targeting exosome secretion may enhance CAR T-cell efficacy. See related commentary by Ortiz-Espinosa and Srivastava, p. 2637.
©2023 American Association for Cancer Research.

The colonic epithelium requires continuous renewal by crypt resident intestinal stem cells (ISCs) and transit-amplifying (TA) cells to maintain barrier integrity, especially after inflammatory damage. The diet of high-income countries contains increasing amounts of sugar, such as sucrose. ISCs and TA cells are sensitive to dietary metabolites, but whether excess sugar affects their function directly is unknown.
Here, we used a combination of 3-dimensional colonoids and a mouse model of colon damage/repair (dextran sodium sulfate colitis) to show the direct effect of sugar on the transcriptional, metabolic, and regenerative functions of crypt ISCs and TA cells.
We show that high-sugar conditions directly limit murine and human colonoid development, which is associated with a reduction in the expression of proliferative genes, adenosine triphosphate levels, and the accumulation of pyruvate. Treatment of colonoids with dichloroacetate, which forces pyruvate into the tricarboxylic acid cycle, restored their growth. In concert, dextran sodium sulfate treatment of mice fed a high-sugar diet led to massive irreparable damage that was independent of the colonic microbiota and its metabolites. Analyses on crypt cells from high-sucrose-fed mice showed a reduction in the expression of ISC genes, impeded proliferative potential, and increased glycolytic potential without a commensurate increase in aerobic respiration.
Taken together, our results indicate that short-term, excess dietary sucrose can directly modulate intestinal crypt cell metabolism and inhibit ISC/TA cell regenerative proliferation. This knowledge may inform diets that better support the treatment of acute intestinal injury.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Two-dimensional nanostructures have gained tremendous interest in the field of biomedical applications and cancer activity in particular. Although sulfur is known for its wide range of biological activities, its potentiality in two-dimensional forms as an antitumor agent is hitherto unexplored. To address the current deficient knowledge on nano-sulfur as an antitumor agent, we report the synthesis of nano-sulfur sheets/particles and their cytotoxic, apoptotic activity against human carcinoma cell lines. In vitro cytotoxic effects of biogenic nanosheets (SNP-B) and chemogenic nanoparticles (SNP-C) were assessed against human lung carcinoma (A549), human epidermoid carcinoma (A431), human promyelocytic leukaemia (HL60) and human lung fibroblast (IMR90) cell lines. Cell cycle analysis, apoptotic study, and caspase-3 expression studies were carried out to understand the mechanism of cytotoxic activity of nano-sulfur. The MTT assay indicated a dose-dependent decrease in viability of all the cell lines treated with nano-sulfur, with SNP-B being more toxic compared to SNP-C. The apoptotic study and cell cycle analysis indicated cell cycle arrest followed by apoptosis-induced cell death. The caspase-3 expression study indicated that nano-sulfur induces apoptosis by the activation of caspase through the mitochondrial pathway. Apart from this, a lower cytotoxicity was observed in IMR90 cell lines treated with SNP-B , indicating a higher specificity of synthesized nanosheets towards cancer cells. Taken all together, this work highlights the potentiality of sulfur nanosheets in inducing cytotoxicity and apoptotic activity, and the impact of morphology as a critical determinant on the cytotoxic response on various cell lines.
© 2021 The Authors. Published by American Chemical Society.

The colonic epithelium requires continuous renewal by intestinal stem cells (ISCs) to restore the barrier after damage and proliferation of epithelial cells is modulated by dietary metabolites. We demonstrate that mice fed a high sugar diet failed to repair colonic barrier damage, resulting in increased intestinal pathology. Culturing ISCs in excess sugar limited murine and human colonoid development, indicating that dietary sugar can directly affect colonic epithelial proliferation. Similarly, in vivo lineage tracing experiments and transcriptomic analysis indicated that dietary sugar impeded the proliferative potential of ISCs. ISCs and their immediate daughter cells predominantly rely on mitochondrial respiration for energy; however, metabolic analysis of colonic crypts revealed that a high sugar diet primed the epithelium for glycolysis without a commensurate increase in aerobic respiration. Colonoids cultured in high-glucose conditions accumulated glycolytic metabolites but not TCA cycle intermediates, indicating that the two metabolic pathways may not be coupled in proliferating intestinal epithelium. Accordingly, biochemically inducing pyruvate flux through the TCA cycle by inhibiting pyruvate dehydrogenase kinase rescued sugar-impaired colonoid development. Our results indicate that excess dietary sugar can directly inhibit epithelial proliferation in response to damage and may inform diets that better support the treatment of acute intestinal injury.