Targeting LGSN restores sensitivity to chemotherapy in gastric cancer stem cells by triggering pyroptosis.

Gastric cancer (GC) is notoriously resistant to current therapies due to tumor heterogeneity. Cancer stem cells (CSCs) possess infinite self-renewal potential and contribute to the inherent heterogeneity of GC. Despite its crucial role in chemoresistance, the mechanism of stemness maintenance of gastric cancer stem cells (GCSCs) remains largely unknown. Here, we present evidence that lengsin, lens protein with glutamine synthetase domain (LGSN), a vital cell fate determinant, is overexpressed in GCSCs and is highly correlated with malignant progression and poor survival in GC patients. Ectopic overexpression of LGSN in GCSC-derived differentiated cells facilitated their dedifferentiation and treatment resistance by interacting with vimentin and inducing an epithelial-to-mesenchymal transition. Notably, genetic interference of LGSN effectively suppressed tumor formation by inhibiting GCSC stemness maintenance and provoking gasdermin-D-mediated pyroptosis through vimentin degradation/NLRP3 signaling. Depletion of LGSN combined with the chemo-drugs 5-fluorouracil and oxaliplatin could offer a unique and promising approach to synergistically rendering this deadly cancer eradicable in vivo. Our data place focus on the role of LGSN in GCSC regeneration and emphasize the critical importance of pyroptosis in battling GCSC.

[Research Progress in Immunosuppressive Tumor Microenvironment of Gastrointestinal Cancer].

Gastrointestinal (GI) cancer, a common malignant tumor with a high incidence in China, is showing a trend of rising incidence and is afflicting increasingly younger patients. Meanwhile, there have been constant development and innovations in new therapeutic technologies, among which, immunotherapy is now leading in a new era in the treatment of GI cancer. However, the complexity and diversity of immunosuppressive tumor microenvironment (TME) bring many obstacles to the immunotherapy of solid tumors in the GI tract. In this paper, focusing on solid tumors in the GI tract, we reviewed the main factors affecting the formation of immunosuppressive TME, and summarized strategies for targeted immunosuppressive TME-based therapies. Moreover, we analyzed the synergistic mechanism of various combination immunotherapies and reported on the latest progress in and future direction of immunotherapy for GI cancer, intending to provide new perspectives for treating solid tumors in the GI tract with immumotherapy.